Table name:
Figure 2: Effect of venlafaxine on the pharmacokinetics interacting drugs and their active metabolites.


Table name:
Interacting Drug Interaction
Drugs known to prolong QT interval (e.g., Class IA and Class III antiarrhythmic agents). Quinine sulfate capsules prolong QT interval, ECG abnormalities including QT prolongation and Torsades de pointes. Avoid concomitant use. (5.3)
Other antimalarials (e.g., halofantrine, mefloquine). ECG abnormalities including QT prolongation. Avoid concomitant use. (5.3, 7.2)
CYP3A4 inducers or inhibitors Alteration in plasma quinine concentration. Monitor for lack of efficacy or increased adverse events of quinine. (7.1)
CYP3A4 and CYP2D6 substrates Quinine is an inhibitor of CYP3A4 and CYP2D6. Monitor for lack of efficacy or increased adverse events of the coadministered drug. (7.2)
Digoxin Increased digoxin plasma concentration. (5.8, 7.1)


Table name:
Drugs that Affect Renal Function A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDS], COX-2 inhibitors may impair the excretion of digoxin.
Antiarrthymics Dofetilide Concomitant administration with digoxin was associated with a higher rate of torsades de pointes
Sotalol Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
Dronedarone Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone Analog Teriparatide Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement Thyroid Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics Epinephrine
Norepinephrine     
Dopamine
Can increase the risk of cardiac arrhythmias
Neuromuscular Blocking Agents      Succinylcholine May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.
Supplements Calcium If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.


Table name:
AED Coadministered AED Concentration Topiramate Concentration
Phenytoin
NC or 25% increase Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
48% decrease


Carbamazepine (CBZ)
NC
40% decrease
CBZ epoxide Is not administered but is an active metabolite of carbamazepine.
NC
NE
Valproic acid
11% decrease
14% decrease
Phenobarbital
NC
NE
Primidone
NC
NE
Lamotrigine
NC at TPM doses up to 400 mg/day
13% decrease


Table name:
Drugs That Interfere with Hemostasis
Clinical Impact: • Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of naproxen or naproxen sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: Concomitant use of naproxen or naproxen sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen or naproxen sodium is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE-inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: • During concomitant use of naproxen or naproxen sodium and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of naproxen or naproxen sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen or naproxen sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact: The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of naproxen or naproxen sodium and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen or naproxen sodium and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of naproxen or naproxen sodium and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of naproxen or naproxen sodium and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of naproxen or naproxen sodium and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of naproxen or naproxen sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of naproxen or naproxen sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact: Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention: Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen or naproxen sodium is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed release tablets are not recommended.
Cholestyramine
Clinical Impact: Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention: Concomitant administration of cholestyramine with naproxen or naproxen sodium is not recommended.
Probenecid
Clinical Impact: Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention: Patients simultaneously receiving naproxen or naproxen sodium and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact: Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention: Patients simultaneously receiving naproxen or naproxen sodium and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.


Table name:
Drugs That Interfere with Hemostasis
Clinical Impact: • Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of naproxen or naproxen sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: Concomitant use of naproxen or naproxen sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen or naproxen sodium is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE-inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: • During concomitant use of naproxen or naproxen sodium and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of naproxen or naproxen sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen or naproxen sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact: The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of naproxen or naproxen sodium and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen or naproxen sodium and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of naproxen or naproxen sodium and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of naproxen or naproxen sodium and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of naproxen or naproxen sodium and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of naproxen or naproxen sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of naproxen or naproxen sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact: Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention: Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen or naproxen sodium is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed release tablets are not recommended.
Cholestyramine
Clinical Impact: Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention: Concomitant administration of cholestyramine with naproxen or naproxen sodium is not recommended.
Probenecid
Clinical Impact: Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention: Patients simultaneously receiving naproxen or naproxen sodium and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact: Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention: Patients simultaneously receiving naproxen or naproxen sodium and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.


Table name:
Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.*
*  Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol,felodipinenorfloxacin
   systemic and inhaledfinasterideofloxacin
amoxicillinhydrocortisoneomeprazole
ampicillin,isofluraneprednisone, prednisolone
   with or without sulbactamisoniazidranitidine
atenololisradipinerifabutin
azithromycininfluenza vaccineroxithromycin
caffeine,ketoconazolesorbitol
dietary ingestionlomefloxacin   (purgative doses do not
cefaclormebendazole   inhibit theophylline
co-trimoxazolemedroxyprogesterone   absorption)
   (trimethoprimmethylprednisolonesucralfate
   sulfamethoxazole)metronidazoleterbutaline, systemic
diltiazemmetoprololterfenadine
dirithromycinnadololtetracycline
enfluranenifedipinetocainide
famotidinenizatidine


Table name:
Table 4: Clinically Relevant Interactions Affecting Omeprazole When Co-Administered with Other Drugs
CYP2C19 or CYP3A4 Inducers
Clinical Impact:
Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology (12.3)].
Intervention:
St. John’s Wort, rifampin: Avoid concomitant use with omeprazole [see Warnings and Precautions (5.9)].
Ritonavir-containing products: see prescribing information for specific drugs.
CYP2C19 or CYP3A4 Inhibitors
Clinical Impact:
Increased exposure of omeprazole [see Clinical Pharmacology (12.3)].
Intervention:
Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered.
 
See prescribing information for voriconazole.


Table name:
Table 2 Clinically Significant Drug Interactions with Indomethacin
Drugs That Interfere with Hemostasis
Clinical Impact: Indomethacin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of indomethacin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of indomethacin extended-release capsules with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].
Intervention: Concomitant use of indomethacin extended-release capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. Indomethacin extended-release capsules are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: During concomitant use of indomethacin extended-release capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of indomethacin extended-release capsules and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. It has been reported that the addition of triamterene to a maintenance schedule of indomethacin extended-release capsules resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin extended-release capsules and triamterene should not be administered together. Both indomethacin extended-release capsules and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin extended-release capsules and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently.
Intervention: Indomethacin and triamterene should not be administered together. During concomitant use of indomethacin extended-release capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects. Be aware that indomethacin and potassium-sparing diuretics may both be associated with increased serum potassium levels [see Warnings and Precautions (5.6)].
Digoxin
Clinical Impact: The concomitant use of indomethacin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of indomethacin extended-release capsules and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of indomethacin extended-release capsules and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of indomethacin extended-release capsules and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of indomethacin extended-release capsules and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of indomethacin extended-release capsules and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)]. Combined use with diflunisal may be particularly hazardous because diflunisal causes significantly higher plasma levels of indomethacin [see Clinical Pharmacology (12.3)]. In some patients, combined use of indomethacin and diflunisal has been associated with fatal gastrointestinal hemorrhage.
Intervention: The concomitant use of indomethacin with other NSAIDs or salicylates, especially diflunisal, is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of indomethacin extended-release capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of indomethacin extended-release capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Probenecid
Clinical Impact: When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased.
Intervention: During the concomitant use of indomethacin extended-release capsules and probenecid, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect. When increases in the dose of indomethacin are made, they should be made carefully and in small increments.


Table name:
Antiretrovirals
        Clinical Impact: The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology (12.3)]. Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see Clinical Pharmacology (12.3)]. There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole.
        Intervention: Rilpivirine-containing products: Concomitant use with omeprazole is contraindicated [see Contraindications (4)].

Atazanavir: Avoid concomitant use with omeprazole. See prescribing information for atazanavir for dosing information.

Nelfinavir: Avoid concomitant use with omeprazole. See prescribing information for nelfinavir.

Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities.

Other antiretrovirals: See prescribing information for specific antiretroviral drugs.
Warfarin
Clinical Impact: Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
Intervention: Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range.
Methotrexate
Clinical Impact: Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions (5.11)].
Intervention: A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate.
CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam)
Clopidogrel
Clinical Impact: Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology (12.3)].

There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel.
Intervention: Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy [see Warnings and Precautions (5.6)].
Citalopram
Clinical Impact: Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology (12.3)].
Intervention: Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.
Cilostazol
Clinical Impact: Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology (12.3)].
Intervention: Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.
Phenytoin
Clinical Impact: Potential for increased exposure of phenytoin.
Intervention: Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin.
Diazepam
Clinical Impact: Increased exposure of diazepam [see Clinical Pharmacology (12.3)].
Intervention: Monitor patients for increased sedation and reduce the dose of diazepam as needed.
Digoxin
Clinical Impact: Potential for increased exposure of digoxin [see Clinical Pharmacology (12.3)].
Intervention: Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)
Clinical Impact: Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
     Intervention: Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF [see Clinical Pharmacology (12.3)].

See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact: Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated.
Amoxicillin also has drug interactions.
Intervention: See Contraindications, Warnings and Precautions in prescribing information for clarithromycin.

See Drug Interactions in prescribing information for amoxicillin.
Tacrolimus
Clinical Impact: Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.
Intervention: Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact: Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions (5.10), Clinical Pharmacology (12.2)].
  Intervention: Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
Interaction with Secretin Stimulation Test
Clinical Impact: Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention: Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology (12.2)].
False Positive Urine Tests for THC
Clinical Impact: There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.
Intervention: An alternative confirmatory method should be considered to verify positive results.
Other
Clinical Impact: There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram).
Intervention: Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole.


Table name:
Antiretrovirals
        Clinical Impact: The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology ( 12.3)] . Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see Clinical Pharmacology ( 12.3)] . There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole.
        Intervention: Rilpivirine-containing products: Concomitant use with omeprazole is contraindicated [see Contraindications ( 4)] .

Atazanavir: Avoid concomitant use with omeprazole. See prescribing information for atazanavir for dosing information.

Nelfinavir: Avoid concomitant use with omeprazole. See prescribing information for nelfinavir.

Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities.

Other antiretrovirals: See prescribing information for specific antiretroviral drugs.
Warfarin
Clinical Impact: Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
Intervention: Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range.
Methotrexate
Clinical Impact: Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions ( 5.11)] .
Intervention: A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate.
CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam)
Clopidogrel
Clinical Impact: Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology ( 12.3)] .

There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel.
Intervention: Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy [see Warnings and Precautions ( 5.6)] .
Citalopram
Clinical Impact: Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology ( 12.3)] .
Intervention: Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.
Cilostazol
Clinical Impact: Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology ( 12.3)] .
Intervention: Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.
Phenytoin
Clinical Impact: Potential for increased exposure of phenytoin.
Intervention: Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin.
Diazepam
Clinical Impact: Increased exposure of diazepam [see Clinical Pharmacology ( 12.3)] .
Intervention: Monitor patients for increased sedation and reduce the dose of diazepam as needed.
Digoxin
Clinical Impact: Potential for increased exposure of digoxin [see Clinical Pharmacology ( 12.3)] .
Intervention: Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)
Clinical Impact: Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
     Intervention: Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF [see Clinical Pharmacology ( 12.3)] .

See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact: Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated.
Amoxicillin also has drug interactions.
Intervention: See Contraindications, Warnings and Precautions in prescribing information for clarithromycin.

See Drug Interactions in prescribing information for amoxicillin.
Tacrolimus
Clinical Impact: Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.
Intervention: Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact: Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions ( 5.10), Clinical Pharmacology ( 12.2)] .
  Intervention: Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
Interaction with Secretin Stimulation Test
Clinical Impact: Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention: Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology ( 12.2)] .
False Positive Urine Tests for THC
Clinical Impact: There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.
Intervention: An alternative confirmatory method should be considered to verify positive results.
Other
Clinical Impact: There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram).
Intervention: Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole.


Table name:
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.4)].
Examples: Benzodiazepines and other sedative hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue morphine sulfate extended-release tablets if serotonin syndrome is suspected.
Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.6)].
Intervention: Do not use morphine sulfate extended-release tablets in patients taking MAOIs or within 14 days of stopping such treatment.
Examples: phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact: May reduce the analgesic effect of morphine sulfate extended-release tablets and/or precipitate withdrawal symptoms.
Intervention: Avoid concomitant use.
Examples: butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact: Morphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of morphine sulfate extended-release tablets and/or the muscle relaxant as necessary.
Cimetidine
Clinical Impact: The concomitant use of cimetidine can potentiate morphine effects and increase risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of morphine sulfate extended-release tablets and/or cimetidine as necessary.
Diuretics
Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when morphine sulfate extended-release tablets are used concomitantly with anticholinergic drugs.
P-Glycoprotein (P-gp) Inhibitors
Clinical Impact: The concomitant use of PGP-inhibitors can increase the exposure to morphine by about two-fold and can increase risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of morphine sulfate extended-release tablets and/or the PGP-inhibitor as necessary.
Example: quinidine


Table name:
AED Coadministered AED Concentration Topiramate Concentration
Phenytoin
NC or 25% increase Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
48% decrease


Carbamazepine (CBZ)
NC
40% decrease
CBZ epoxide Is not administered but is an active metabolite of carbamazepine.
NC
NE
Valproic acid
11% decrease
14% decrease
Phenobarbital
NC
NE
Primidone
NC
NE
Lamotrigine
NC at TPM doses up to 400 mg/day
13% decrease


Table name:
Drugs That Interfere with Hemostasis
Clinical Impact: • Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of naproxen or naproxen sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: Concomitant use of naproxen or naproxen sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen or naproxen sodium is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE-inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: • During concomitant use of naproxen or naproxen sodium and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of naproxen or naproxen sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen or naproxen sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact: The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of naproxen or naproxen sodium and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen or naproxen sodium and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of naproxen or naproxen sodium and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of naproxen or naproxen sodium and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of naproxen or naproxen sodium and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of naproxen or naproxen sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of naproxen or naproxen sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact: Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention: Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen or naproxen sodium is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed release tablets are not recommended.
Cholestyramine
Clinical Impact: Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention: Concomitant administration of cholestyramine with naproxen or naproxen sodium is not recommended.
Probenecid
Clinical Impact: Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention: Patients simultaneously receiving naproxen or naproxen sodium and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact: Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention: Patients simultaneously receiving naproxen or naproxen sodium and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.


Table name:
 Drugs that Affect Renal Function  A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDS], COX-2 inhibitors may impair the excretion of digoxin.
 Antiarrthymics  Dofetilide  Concomitant administration with digoxin was associated with a higher rate of torsades de pointes
   Sotalol  Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
   Dronedarone  Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
 Parathyroid Hormone Analog  Teriparatide  Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
 Thyroid supplement  Thyroid  Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
 Sympathomimetics  Epinephrine
Norepinephrine     
Dopamine
 Can increase the risk of cardiac arrhythmias
 Neuromuscular Blocking Agents       Succinylcholine  May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.
 Supplements  Calcium  If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
 Beta-adrenergic blockers and calcium channel blockers    Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.


Table name:
Table 4. Mean (95% C.I.) maximal change in baseline in systolic blood pressure (mmHg) following vardenafil 10 and 20 mg in healthy volunteers on daily alpha-blocker therapy
Dosing of Vardenafil and Alpha-Blocker Separated by 6 Hours Simultaneous dosing of Vardenafil and Alpha-Blocker
Alpha-Blocker Vardenafil
10 mg
Placebo-Subtracted
Vardenafil
20 mg
Placebo-Subtracted
Vardenafil
10 mg
Placebo-Subtracted
Vardenafil
20 mg
Placebo-Subtracted
Terazosin
10 mg daily
Standing SBP -7 (-10, -3) -11 (-14, -7) -23 (-31, 16) Due to the sample size, confidence intervals may not be an accurate measure for these data. These values represent the range for the difference. -14 (-33, 11)
Supine SBP -5 (-8, -2) -7 (-11, -4) -7 (-25, 19) -7 (-31, 22)
Tamsulosin
0.4 mg daily
Standing SBP -4 (-8, -1) -8 (-11, -4) -8 (-14, -2) -8 (-14, -1)
Supine SBP -4 (-8, 0) -7 (-11, -3) -5 (-9, -2) -3 (-7, 0)


Table name:
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Drugs that May Increase the Risk of Hypoglycemia
Drugs: Antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, salicylates, somatostatin analog (e.g., octreotide), and sulfonamide antibiotics
Intervention: Dose adjustment and increased frequency of glucose monitoring may be required when NOVOLOG MIX 70/30 is co-administered with these drugs.
Drugs that May Decrease the Blood Glucose Lowering Effect of NOVOLOG MIX 70/30
Drugs: Atypical antipsychotics (e.g., olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones.
Intervention: Dose adjustment and increased frequency of glucose monitoring may be required when NOVOLOG MIX 70/30 is co-administered with these drugs.
Drugs that May Increase or Decrease the Blood Glucose Lowering Effect ofNOVOLOG MIX 70/30
Drugs: Alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia.
Intervention: Dose adjustment and increased frequency of glucose monitoring may be required when NOVOLOG MIX 70/30 is co-administered with these drugs.
Drugs that May Blunt Signs and Symptoms of Hypoglycemia
Drugs: Beta-blockers, clonidine, guanethidine, and reserpine
Intervention: Increased frequency of glucose monitoring may be required when NOVOLOG MIX 70/30 is co-administered with these drugs.


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T 4 and T 3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin/Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens/Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non-Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT 4 . Continued administration results in a decrease in serum T 4 and normal FT 4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T 4 and T 3 to TBG and transthyretin. An initial increase in serum FT 4 is followed by return of FT 4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T 4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T 4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ³ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T 4 to T 3, leading to decreased T 3 levels. However, serum T 4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T 3 and T 4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T 3 concentrations by 30% with minimal change in serum T 4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T 3 and T 4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias
and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123 I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on
Concentration of Lamotrigine or Concomitant Drug
Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine Decreased lamotrigine concentrations approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? carbamazepine epoxide May increase carbamazepine epoxide levels.
 Lopinavir/ritonavir ↓ lamotrigine Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir ↓ lamotrigine Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine
Increased lamotrigine concentrations slightly more than 2-fold.
? valproate There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.


Table name:
Drugs That Interfere with Hemostasis
Clinical Impact: Indomethacin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of indomethacin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of indomethacin with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ see Warnings and Precautions ( 5.11 )].
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ see Warnings and Precautions ( 5.2 ) ].
Intervention: Concomitant use of indomethacin capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions ( 5.11 )].Indomethacin is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: During concomitant use of indomethacin capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.During concomitant use of indomethacin capsules and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ see Warnings and Precautions ( 5.6 )].When these drugs are administered concomitantly, patients should be adequately hydrated.  Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.It has been reported that the addition of triamterene to a maintenance schedule of Indomethacin resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin and triamterene should not be administered together.Both indomethacin and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently [ see Warnings and Precautions ( 5.6 )].  
Intervention: Indomethacin and triamterene should not be administered together. During concomitant use of indomethacin capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects. Be aware that indomethacin and potassium-sparing diuretics may both be associated with increased serum potassium levels. [ see Warnings and Precautions ( 5.6 )].  
Digoxin  
Clinical Impact: The concomitant use of indomethacin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.  
Intervention: During concomitant use of indomethacin capsules and digoxin, monitor serum digoxin levels.  
Lithium  
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.  
Intervention: During concomitant use of indomethacin capsules and lithium, monitor patients for signs of lithium toxicity.  
Methotrexate  
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).  
Intervention: During concomitant use of indomethacin capsules and methotrexate, monitor patients for methotrexate toxicity.  
Cyclosporine  
Clinical Impact: Concomitant use of indomethacin capsules and cyclosporine may increase cyclosporine's nephrotoxicity.  
Intervention: During concomitant use of indomethacin capsules and cyclosporine, monitor patients for signs of worsening renal function.  
NSAIDs and Salicylates  
Clinical Impact: Concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ see Warnings and Precautions ( 5.2 )]. Combined use with diflunisal may be particularly hazardous because diflunisal causes significantly higher plasma levels of indomethacin [see Clinical Pharmacology ( 12.3 )].In some patients, combined use of indomethacin and diflunisal has been associated with fatal gastrointestinal hemorrhage.  
Intervention: The concomitant use of indomethacin with other NSAIDs or salicylates, especially diflunisal, is not recommended.  
Pemetrexed  
Clinical Impact: Concomitant use of indomethacin capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).  
Intervention: During concomitant use of indomethacin capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.  
Probenecid  
Clinical Impact: When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased.  
Intervention: During the concomitant use of indomethacin and probenecid, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect.  When increases in the dose of indomethacin are made, they should be made carefully and in small increments.  


Table name:
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
a = Plasma concentration increased 25% in some patients, generally
      those on a twice a day dosing regimen of phenytoin.
b = Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated.
   AED
Co-administered   
AED Concentration
Topiramate
   Concentration   
 Phenytoin
NC or 25% increasea
48% decrease
 Carbamazepine (CBZ) 
NC
40% decrease
 CBZ epoxideb
NC
NE
 Valproic acid
11% decrease
14% decrease
 Phenobarbital
NC
NE
 Primidone
NC
NE
 Lamotrigine
   NC at TPM doses up to 400 mg/day   
13% decrease


Table name:
Drug Description of Interaction
Tolbutamide; Sulfonylureas Hypoglycemia potentiated
Methotrexate Decreases tubular reabsorption; clinical toxicity from methotrexate can result
Oral Anticoagulant Increased bleeding


Table name:
 Interacting Drug  Interaction
 Antacids, sucralfate, multivitamins, and other products containing multivalent cations  Moxifloxacin absorption is decreased. Administer moxifloxacin hydrochloride tablet at least 4 hours before or 8 hours after these products. (2.2, 7.1, 12.3, 17.2)
 Warfarin  Anticoagulant effect of warfarin may be enhanced. Monitor prothrombin time/INR, watch for bleeding. (6.4, 7.2, 12.3)
 Class IA and Class III antiarrhythmics:  Proarrhythmic effect may be enhanced. Avoid concomitant use. (5.3, 7.4)


Table name:
Specific Drugs Reported
also: other medications affecting blood elements which may modify hemostasis
dietary deficiencies
prolonged hot weather
unreliable PT/INR determinations
†Increased and decreased PT/INR responses have been reported.
acetaminophen
alcohol†
allopurinol
aminosalicylic acid
amiodarone HCl
argatroban
aspirin
atenolol
atorvastatin†
azithromycin
bivalirudin
capecitabine
cefamandole
cefazolin
cefoperazone
cefotetan
cefoxitin
ceftriaxone
celecoxib
cerivastatin
chenodiol
chloramphenicol
chloral hydrate†
chlorpropamide
cholestyramine†
cimetidine
ciprofloxacin
cisapride
clarithromycin
clofibrate
cyclophosphamide†
danazol
dextran
dextrothyroxine
diazoxide
diclofenac
dicumarol
diflunisal
disulfiram
doxycycline
erythromycin
esomeprazole
ethacrynic acid
ezetimibe
fenofibrate
fenoprofen
fluconazole
fluorouracil
fluoxetine
flutamide
fluvastatin
fluvoxamine
gefitinib
gemifibrozil
glucagon
halothane
heparin
ibuprofen
ifosfamide
indomethacin
influenza virus vaccine
itraconazole
ketoprofen
ketorolac
lansoprazole
lepirudin
levamisole
levofloxacin
levothyroxine
liothyronine
lovastatin
mefenamic acid
methimazole†
methyldopa
methylphenidate
methylsalicylate
ointment (topical)
metronidazole
miconazole
(intravaginal, oral,
systemic)
moricizine
hydrochloride†
nalidixic acid
naproxen
neomycin
norfloxacin
ofloxacin
olsalazine
omeprazole
oxandrolone
oxaprozin
oxymetholone
pantoprazole
paroxetine
penicillin G,
intravenous
pentoxifylline
phenylbutazone
phenytoin†
piperacillin
piroxicam
pravastatin†
prednisone†
propafenone
propoxyphene
propranolol
propylthiouracil†
quinidine
quinine
rabeprazole
ranitidine†
rofecoxib
sertraline
simvastatin
stanozolol
streptokinase
sulfamethizole
sulfamethoxazole
sulfinpyrazone
sulfisoxazole
sulindac
tamoxifen
tetracycline
thyroid
ticarcillin
ticlopidine
tissue plasminogen
activator (t-PA)
tolbutamide
tramadol
trimethoprim/
sulfamethoxazole
urokinase
valdecoxib
valproate
vitamin E
warfarin overdose
zafirlukast
zileuton


Table name:
Table 18Summary of Effect of Coadministered Drugs on Exposure to Active Moiety(Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients withSchizophrenia
*Change relative to reference
Coadministered Drug
Dosing Schedule

Effect on Active
Moiety
(Risperidone + 9-
Hydroxy-
Risperidone (Ratio*)

Risperidone Dose
Recommendation

Coadministered Drug
Risperidone
AUC
Cm a x

Enzyme (CYP2D6) 
Inhibitors 





Fluoxetine 
20 mg/day
2 or 3 mg twice
daily
1.4
1.5
Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine 
10 mg/day
4 mg/day
1.3
-
Re-evaluate dosing. 







20 mg/day
4 mg/day
1.6
-
Do not exceed 8 mg/day

40 mg/day
4 mg/day
1.8
-

Enzyme (CYP3A/ 
PgP inducers) inducers





Carbamazepine 
573 ± 168 mg/day
3 mg twice daily
0.51
0.55
Titrate dose upwards.
Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) 
Inhibitors 





Ranitidine 
150 mg twice daily
1 mg single dose
1.2
1.4
Dose adjustment not
needed
Cimetidine 
400 mg twice daily
1 mg single dose
1.1
1.3
Dose adjustment not
needed
Erythromycin 
500 mg four times
daily
1 mg single dose
1.1
0.94
Dose adjustment not
needed
Other Drugs 





Amitriptyline 
50 mg twice daily
3 mg twice daily
1.2
1.1
Dose adjustment not
needed


Table name:
Drugs That Interfere with Hemostasis
Clinical Impact: • Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of naproxen or naproxen sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: Concomitant use of naproxen or naproxen sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen or naproxen sodium is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE-inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: • During concomitant use of naproxen or naproxen sodium and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of naproxen or naproxen sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen or naproxen sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact: The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of naproxen or naproxen sodium and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen or naproxen sodium and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of naproxen or naproxen sodium and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of naproxen or naproxen sodium and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of naproxen or naproxen sodium and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of naproxen or naproxen sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of naproxen or naproxen sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact: Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention: Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen or naproxen sodium is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed release tablets are not recommended.
Cholestyramine
Clinical Impact: Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention: Concomitant administration of cholestyramine with naproxen or naproxen sodium is not recommended.
Probenecid
Clinical Impact: Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention: Patients simultaneously receiving naproxen or naproxen sodium and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact: Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention: Patients simultaneously receiving naproxen or naproxen sodium and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.


Table name:
TABLE 2. Mean (± S.D.) Pharmacokinetic Parameters for Estradiol, Estrone, and Equilin Following Coadministration of Conjugated Estrogens 0.625 mg and PROMETRIUM Capsules 200 mg for 12 Days to Postmenopausal Women
a Total estrogens is the sum of conjugated and unconjugated estrogen.
  Conjugated Estrogens Conjugated Estrogens plus PROMETRIUM Capsules
Drug Cmax
(ng/mL)
Tmax
(hr)
AUC(0-24h)
(ng × h/mL)
Cmax
(ng/mL)
Tmax
(hr)
AUC(0-24h)
(ng × h/mL)
Estradiol 0.037
± 0.048
12.7
± 9.1
0.676
± 0.737
0.030
± 0.032
17.32
± 1.21
0.561
± 0.572
Estrone
Total a
3.68
± 1.55
10.6
± 6.8
61.3
± 26.36
4.93
± 2.07
7.5
± 3.8
85.9
± 41.2
Equilin
Total a
2.27
± 0.95
6.0
± 4.0
28.8
± 13.0
3.22
± 1.13
5.3
± 2.6
38.1
± 20.2


Table name:
Table 4 Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table 5 for Magnitude of Interaction.
Drug Name Effect on Concentration of Nevirapine or Concomitant Drug Clinical Comment
Atazanavir/Ritonavir ↓ Atazanavir

↑ Nevirapine
Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure.
Clarithromycin ↓ Clarithromycin

↑ 14-OH clarithromycin
Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased.  Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex , overall activity against this pathogen may be altered.  Alternatives to clarithromycin, such as azithromycin, should be considered.
Efavirenz ↓ Efavirenz There has been no determination of appropriate doses for the safe and effective use of this combination [ see Warnings and Precautions (5.4) ].
Ethinyl estradiol and Norethindrone ↓ Ethinyl estradiol

↓ Norethindrone
Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications.  An alternative or additional method of contraception is recommended.
Fluconazole ↑Nevirapine Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events.
Fosamprenavir ↓ Amprenavir

↑ Nevirapine
Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.
Fosamprenavir/Ritonavir ↓ Amprenavir

↑ Nevirapine
No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily.
Indinavir ↓ Indinavir Appropriate doses for this combination are not established, but an increase in the dosage of indinavir may be required.
Ketoconazole ↓ Ketoconazole Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.
Lopinavir/Ritonavir ↓Lopinavir Lopinavir/ritonavir 400/100 mg tablets can be used twice daily in combination with nevirapine with no dose adjustment in antiretroviral-naïve patients.

A dose increase of lopinavir/ritonavir tablets to 600/150 mg (3 tablets) twice daily may be considered when used in combination with nevirapine in treatment-experienced patients where decreased susceptibility to lopinavir is clinically suspected (by treatment history or laboratory evidence).

A dose increase of lopinavir/ritonavir oral solution to 533/133 mg twice daily with food is recommended in combination with nevirapine.

In children 6 months to 12 years of age, consideration should be given to increasing the dose of lopinavir/ritonavir to 13/3.25 mg/kg for those 7 to <15 kg; 11/2.75 mg/kg for those 15 to 45 kg; and up to a maximum dose of 533/133 mg for those >45 kg twice daily when used in combination with nevirapine, particularly for patients in whom reduced susceptibility to lopinavir/ritonavir is suspected.
Methadone ↓ Methadone Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal.  Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Nelfinavir ↓Nelfinavir M8 Metabolite
↓Nelfinavir Cmin
The appropriate dose for nelfinavir in combination with nevirapine, with respect to safety and efficacy, has not been established.
Rifabutin ↑Rifabutin Rifabutin and its metabolite concentrations were moderately increased.  Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity.  Therefore, caution should be used in concomitant administration.
Rifampin   ↓ Nevirapine Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug.  Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.  
Saquinavir/ritonavir The interaction between VIRAMUNE and saquinavir/ritonavir has not been evaluated The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.

Potential Drug Interactions: 
   
Drug Class Examples of Drugs  
Antiarrhythmics Amiodarone, disopyramide, lidocaine Plasma concentrations may be decreased.
Anticonvulsants Carbamazepine, clonazepam, ethosuximide Plasma concentrations may be decreased.
Antifungals Itraconazole Plasma concentrations of some azole antifungals may be decreased. Nevirapine and itraconazole should not be administered concomitantly due to a potential decrease in itraconazole plasma concentrations.
Calcium channel blockers Diltiazem, nifedipine, verapamil Plasma concentrations may be decreased.
Cancer chemotherapy Cyclophosphamide Plasma concentrations may be decreased.
Ergot alkaloids Ergotamine Plasma concentrations may be decreased.
Immunosuppressants Cyclosporin, tacrolimus, sirolimus Plasma concentrations may be decreased.
Motility agents Cisapride Plasma concentrations may be decreased.
Opiate agonists Fentanyl Plasma concentrations may be decreased.
Antithrombotics Warfarin Plasma concentrations may be increased. Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.


Table name:
Table 3Drugs that Can Increase the Risk of Bleeding
Drug  Class
Specific  Drugs
Anticoagulants 
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin 
Antiplatelet Agents 
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine 
Nonsteroidal Anti-Inflammatory Agents 
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac 
Serotonin Reuptake Inhibitors 
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone 


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may
result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-
   containing radiographic
   contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which
may result in hyperthyroidism
Amiodarone
Iodide (including iodine-
containing Radiographic
contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase Drugs that may decrease
serum TBG concentration serum TBG concentration
Clofibrate Androgens / Anabolic Steroids
Estrogen-containing oral Asparaginase
   contraceptives Glucocorticoids
Estrogens (oral) Slow-Release Nicotinic Acid
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal
Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake
Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
NITROPRUSSIDE
Para-aminosalicylate sodium
Perphenazine
Resorcinol
 (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 3: Clinically Important Drug Interactions with Repaglinide Tablets
Gemfibrozil
Clinical Impact: Gemfibrozil significantly increased repaglinide exposures by 8.1 fold [see Clinical Pharmacology (12.3)]
Intervention: Do not administer repaglinide tablets to patients receiving gemfibrozil [see Contraindications (4)].
Clopidogrel
Clinical Impact: Clopidogrel increased repaglinide exposures by 3.9-5.1 fold [see Clinical Pharmacology (12.3)]
Intervention: Avoid concomitant use of repaglinide tablets with clopidogrel. If concomitant use cannot be avoided, initiate repaglinide tablets at 0.5 mg before each meal and do not exceed a total daily dose of 4 mg [see DOSAGE AND ADMINISTRATION (2.3)]. Increased frequency of glucose monitoring may be required during concomitant use.
Cyclosporine
Clinical Impact: Cyclosporine increased low dose repaglinide exposures by 2.5 fold [see Clinical Pharmacology (12.3)]
Intervention: Daily maximum repaglinide tablets dose should be limited to 6 mg, and increased frequency of glucose monitoring may be required when repaglinide tablets is co-administered with cyclosporine.
CYP2C8 and CYP3A4 Inhibitors
Intervention: Repaglinide tablets dose reductions and increased frequency of glucose monitoring may be required when co-administered.
Examples: Drugs that are known to inhibit CYP3A4 include antifungal agents (ketoconazole, itraconazole) and antibacterial agents (clarithromycin, erythromycin). Drugs that are known to inhibit CYP2C8 include trimethoprim, gemfibrozil, montelukast, deferasirox, and clopidiogrel.
CYP2C8 and CYP3A4 Inducers
Intervention: Repaglinide tablets dose increases and increased frequency of glucose monitoring may be required when co-administered.
Examples: Drugs that induce the CYP3A4 and/or 2C8 enzyme systems include rifampin, barbiturates, and carbamezapine
Drugs That May Increase the Risk of Hypoglycemia
Intervention: Repaglinide tablets dose reductions and increased frequency of glucose monitoring may be required when co-administered.
Examples: Antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, nonsteroidal anti-inflammatory agents (NSAIDs), pentoxifylline, pramlintide, propoxyphene, salicylates, somatostatin analogs (e.g., octreotide), and sulfonamide antibiotics
Drugs That May Decrease the Blood Glucose Lowering Effect of Repaglinide Tablets
Intervention: Repaglinide tablets dose increases and increased frequency of glucose monitoring may be required when co-administered.
Examples: Atypical antipsychotics (e.g., olanzapine and clozapine), calcium channel antagonists, corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones.
Drugs That May Blunt Signs and Symptoms of Hypoglycemia
Intervention: Increased frequency of glucose monitoring may be required when repaglinide tablets are co-administered with these drugs.
Examples: beta-blockers, clonidine, guanethidine, and reserpine


Table name:
Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme
Inhibitors
Inducers
CYP2C9 
amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast
aprepitant, bosentan, carbamazepine, phenobarbital, rifampin 
CYP1A2 
acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton
montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking 
CYP3A4 
alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton
armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide 


Table name:
Interacting Drug Interaction
Antacids, sucralfate, multivitamins, and other products containing multivalent cations Moxifloxacin absorption is decreased. Administer AVELOX Tablet at least 4 hours before or 8 hours after these products. (2.2, 7.1, 12.3, 17.2)
Warfarin Anticoagulant effect of warfarin may be enhanced. Monitor prothrombin time/INR, watch for bleeding. (6.4, 7.2, 12.3)
Class IA and Class III antiarrhythmics: Proarrhythmic effect may be enhanced. Avoid concomitant use. (5.3, 7.4)


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
 Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)  Avoid atorvastatin
 HIV protease inhibitor (lopinavir plus ritonavir)  Use with caution and lowest dose necessary
 Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)  Do not exceed 20 mg atorvastatin daily
 HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
 Do not exceed 40 mg atorvastatin daily


Table name:
Factors Dosage Adjustments for REXULTI (2.5)
Strong CYP2D6* or CYP3A4 inhibitors Administer half of usual dose
Strong/moderate CYP2D6 with Strong/moderate CYP3A4 inhibitors Administer a quarter of usual dose
Known CYP2D6 Poor Metabolizers taking strong/moderate CYP3A4 inhibitors Administer a quarter of usual dose
Strong CYP3A4 inducers Double the usual dose and further adjust based on clinical response


Table name:
AED Coadministered AED Concentration Topiramate Concentration
Phenytoin
NC or 25% increase Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
48% decrease


Carbamazepine (CBZ)
NC
40% decrease
CBZ epoxide Is not administered but is an active metabolite of carbamazepine.
NC
NE
Valproic acid
11% decrease
14% decrease
Phenobarbital
NC
NE
Primidone
NC
NE
Lamotrigine
NC at TPM doses up to 400 mg/day
13% decrease


Table name:
Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s) Recommendation Comments
Tizanidine Contraindicated Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)]
Theophylline Avoid Use
(Plasma Exposure Likely to be Increased and Prolonged)
Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions (5.9)].
Drugs Known to Prolong QT Interval Avoid Use Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.11) and Use in Specific Populations (8.5)].
Oral antidiabetic drugs Use with caution
Glucose-lowering effect potentiated
Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs [see Adverse Reactions (6.1)].
Phenytoin Use with caution
Altered serum levels of phenytoin (increased and decreased)
To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin with phenytoin.
Cyclosporine Use with caution
(transient elevations in serum creatinine)
Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs Use with caution
(Increase in anticoagulant effect)
The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate Use with caution
Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels
Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole Use with caution Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin [see Warnings and Precautions (5.16)].
Clozapine Use with caution Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs Use with caution Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil Use with caution
Two-fold increase in exposure
Monitor for sildenafil toxicity [see Clinical Pharmacology (12.3)].
Duloxetine Avoid Use
Five-fold increase in duloxetine exposure
If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives Use with caution
Reduced clearance resulting in elevated levels and prolongation of serum half-life
Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products) Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2.4)]. Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels) Potentiation of ciprofloxacin toxicity may occur.


Table name:
Table 2: Examples of CYP450 Interactions with Warfarin
 Enzyme  Inhibitors  Inducers
 CYP2C9  amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast  aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
 CYP1A2  acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton  montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
 CYP3A4  alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton  armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
* Change relative to reference
Coadministered Drug
Dosing Schedule
Effect on Active
Moiety (Risperidone + 9-
Hydroxy- Risperidone (Ratio*)
Risperidone Dose
Recommendation
Coadministered Drug
Risperidone
AUC
Cmax
Enzyme (CYP2D6)
Inhibitors
Fluoxetine
20 mg/day 
2 or 3 mg twice
daily
1.4 
1.5
Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine
10 mg/day 
4 mg/day
1.3
-
Re-evaluate dosing. 
20 mg/day 
4 mg/day
1.6
-
Do not exceed 8 mg/day
40 mg/day 
4 mg/day
1.8
-
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine 
573 ± 168 mg/day
3 mg twice daily
0.51 
0.55
Titrate dose upwards.
Do not exceed twice the patient’s usual dose
Enzyme (CYP3A)
Inhibitors
Ranitidine 
150 mg twice daily
1 mg single dose
1.2 
1.4
Dose adjustment not
needed
Cimetidine 
400 mg twice daily
1 mg single dose
1.1 
1.3
Dose adjustment not
needed
Erythromycin 

500 mg four times
daily
1 mg single dose
1.1 
0.94
Dose adjustment not
needed
Other Drugs
Amitriptyline 
50 mg twice daily
3 mg twice daily
1.2 
1.1
Dose adjustment not
needed


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 7.8, 12.3)
Interacting Agents Prescribing Recommendations
Strong CYP3A4 Inhibitors, (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin,
clarithromycin, telithromycin,
HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol
Contraindicated with VYTORIN
Verapamil, diltiazem, dronedarone Do not exceed 10/10 mg VYTORIN daily
Amiodarone, amlodipine, ranolazine Do not exceed 10/20 mg VYTORIN daily
Lomitapide For patients with HoFH, do not exceed 10/20 mg VYTORIN daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 10/40 mg VYTORIN when taking lomitapide.
Grapefruit juice Avoid grapefruit juice


Table name:
Table II. Clinically significant drug interactions with theophylline Refer to PRECAUTIONS, Drug Interactions for further information regarding table. .
Drug Type of Interaction Effect Average effect on steady state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.
Adenosine Theophylline blocks adenosine receptors. Higher doses of adenosine may be required to achieve desired effect.
Alcohol A single large dose of alcohol (3 ml/kg of whiskey) decreases theophylline clearance for up to 24 hours. 30% increase
Allopurinol Decreases theophylline clearance doses ≥600 mg/day. 25% increase at allopurinol
Amino glutethimide Increases theophylline clearance by induction of microsomal enzyme activity. 25% decrease
Carbamazepine Similar to aminoglutethimide. 30% decrease
Cimetidine Decreases theophylline clearance by inhibiting cytochrome P450 1A2. 70% increase
Ciprofloxacin Similar to cimetidine. 40% increase
Clarithromycin Similar to erythromycin. 25% increase
Diazepam Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram Decreases theophylline clearance by inhibiting hydroxylation and demethylation. 50% increase
Enoxacin Similar to cimetidine. 300% increase
Ephedrine Synergistic CNS effects. Increased frequency of nausea, nervousness, and insomnia.
Erythromycin Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3. 35% increase.
Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown. 30% increase
Flurazepam Similar to diazepam. Similar to diazepam.
Fluvoxamine Similar to cimetidine. Similar to cimetidine.
Halothane Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines. Increased risk of ventricular arrhythmias
Interferon, human recombinant alpha-A Decreases theophylline clearance. 100% increase
Isoproterenol (IV) Increases theophylline clearance. 20% decrease
Ketamine Pharmacologic May lower theophylline seizure threshold.
Lithium Theophylline increases renal lithium clearance. Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam Similar to diazepam. Similar to diazepam.
Methotrexate (MTX) Decreases theophylline clearance. 20% increase after low dose MTX, higher dose MTX may have a greater effect.
Mexiletine Similar to disulfiram. 80% increase
Midazolam Similar to diazepam. Similar to diazepam.
Moricizine Increases theophylline clearance. 25% decrease
Pancuronium Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition. Larger dose of pancuronium may be required to achieve neuromuscular blockade.
Pentoxifylline Decreases theophylline clearance. 30% increase
Phenobarbital (PB) Similar to aminoglutethimide. 25% decrease after two weeks of concurrent PB.
Phenytoin Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption. Serum theophylline and phenytoin concentrations decrease about 40%.
Propafenone Decreases theophylline clearance and pharmacologic interaction. 40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Propranolol Similar to cimetidine and pharmacologic interaction. 100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Rifampin Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity. 20-40% decrease
Sulfinpyrazone Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline. 20% decrease
Tacrine Similar to cimetidine, also increases renal clearance of theophylline. 90% increase
Thiabendazole Decreases theophylline clearance. 190% increase
Ticlopidine Decreases theophylline clearance. 60% increase
Troleandomycin Similar to erythromycin. 33-100% increase depending on troleandomycin dose.
Verapamil Similar to disulfiram. 20% increase


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant  Drug
Effect  on  Concentration  of  Lamotrigine  or 
Concomitant  Drug
Clinical  Comment 
↓= Decreased (induces lamotrigine gluronidation).
↑= Increased (inhibits lamotrigine glucuronidation).
?= Conflicting data.
Estrogen-containing oral 
contraceptive preparations 
containing 30 mcg ethinylestradiol 
and 150 mcg levonorgestrel
↓ lamotrigine




Decreased lamotrigine levels 
approximately 50%.




↓ levonorgestrel
Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and 
CBZ epoxide
↓ lamotrigine

Addition of carbamazepine decreases lamotrigine 
concentration approximately 40%.


? CBZ epoxide
May increase CBZ epoxide levels
Phenobarbital/Primidone
↓ lamotrigine
Decreased lamotrigine 
concentration approximately 40%.
Phenytoin (PHT)
↓ lamotrigine
Decreased lamotrigine 
concentration approximately 40%
Rifampin
↓ lamotrigine
Decreased lamotrigine AUC 
approximately 40%
Valproate
↑ lamotrigine

Increased lamotrigine concentrations slightly 
more than 2-fold.


? valproate
Decreased valproate concentrations an average of 
25% over a 3-week period then stabilized in healthy volunteers; 
no change in controlled clinical trials in epilepsy patients.



Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
 Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration  Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
 Drugs that may alter T 4 and T 3 metabolism
 Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table II. Clinically significant drug interactions with theophylline.Refer to PRECAUTIONS, Drug Interactions for further information regarding table.
 Drug  Type of Interaction  Effect Average effect on steady-state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.
 Adenosine  Theophylline blocks adenosine receptors.  Higher doses of adenosine may be required to achieve desired effect.
 Alcohol  A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours.   30% increase
 Allopurinol   Decreases theophylline clearance at allopurinol doses ≥600 mg/day.  25% increase
 Aminoglutethimide  Increases theophylline clearance by induction of microsomal enzyme activity.  25% decrease
 Carbamazepine  Similar to aminoglutethimide.  30% decrease
 Cimetidine  Decreases theophylline clearance by inhibiting cytochrome P450 1A2.  70% increase
 Ciprofloxacin  Similar to cimetidine.  40% increase
 Clarithromycin  Similar to erythromycin.  25% increase
 Diazepam  Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors.  Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
 Disulfiram  Decreases theophylline clearance by inhibiting hydroxylation and demethylation.  50% increase
 Enoxacin  Similar to cimetidine.  300% increase
 Ephedrine  Synergistic CNS effects  Increased frequency of nausea, nervousness, and insomnia.
 Erythromycin  Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3.  35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
 Estrogen  Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown.  30% increase
 Flurazepam  Similar to diazepam.  Similar to diazepam.
 Fluvoxamine  Similar to cimetidine.  Similar to cimetidine.
 Halothane  Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines.   Increased risk of ventricular arrhythmias.
 Interferon, human recombinant alpha-A  Decreases theophylline clearance.  100% increase
 Isoproterenol (IV)  Increase theophylline clearance.  20% increase
 Ketamine  Pharmacologic  May lower theophylline seizure threshold.
 Lithium  Theophylline increases renal lithium clearance.  Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
 Lorazepam  Similar to diazepam.  Similar to diazepam.
 Methotrexate (MTX)  Decreases theophylline clearance.  20% increase after low dose MTX, higher dose MTX may have a greater effect.
 Mexiletine  Similar to disulfiram.  80% increase
 Midazolam  Similar to diazepam.  Similar to diazepam.
 Moricizine  Increases theophylline clearance.  25% decrease
 Pancuronium  Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition.  Larger dose of pancuronium may be required to achieve neuromuscular blockade.
 Pentoxifylline  Decreases theophylline clearance.  30% increase
 Phenobarbital (PB)  Similar to aminoglutethimide.  25% decrease after two weeks of concurrent PB.
 Phenytoin  Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption.  Serum theophylline and phenytoin concentrations decrease about 40%.
 Propafenone  Decreases theophylline clearance and pharmacologic interaction.  40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
 Propranolol  Similar to cimetidine and pharmacologic interaction.  100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
 Rifampin  Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity.  20 to 40% decrease
 Sulfinpyrazone  Increase theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline.  20% increase
 Tacrine  Similar to cimetidine, also increases renal clearance of theophylline.  90% increase
 Thiabendazole  Decreases theophylline clearance.  190% increase
 Ticlopidine  Decreases theophylline clearance.  60% increase
 Troleandomycin  Similar to erythromycin.  33 to 100% increase depending on troleandomycin dose.
 Verapamil  Similar to disulfiram.  20% increase


Table name:
Table 5. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on
Concentration of
Lamotrigine or
Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine


↓ levonorgestrel
Decreased lamotrigine concentrations approximately 50%.

Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide ↓ lamotrigine


? carbamazepine epoxide
Addition of carbamazepine decreases lamotrigine concentration approximately 40%.

May increase carbamazepine epoxide levels.
Lopinavir/ritonavir ↓ lamotrigine Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir ↓ lamotrigine Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine


? valproate
Increased lamotrigine concentrations slightly more than 2-fold.

There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.
↓ = Decreased (induces lamotrigine glucuronidation).
↑ = Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.


Table name:
Concomitant Drug Name or Drug Class Clinical Rationale Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)]. With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin) The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)]. With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Antihypertensive Drugs Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.7)].
Benzodiazepines (e.g., lorazepam) The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.7)] Monitor sedation and blood pressure. Adjust dose accordingly.


Table name:
Table 3. Drugs That May Alter T4 and Triiodothyronine (T3) Serum Transport Without Affecting Free Thyroxine (FT4) Concentration (Euthyroidism)
Drug or Drug Class Effect
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
These drugs may increase serum thyroxine-binding globulin (TBG) concentration.
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
These drugs may decrease serum TBG concentration.
Potential impact (below): Administration of these agents with SYNTHROID results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations.
Salicylates (> 2 g/day) Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total T4 levels may decrease by as much as 30%.
Other drugs:
Carbamazepine
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non-Steroidal Anti-inflammatory Drugs
- Fenamates
These drugs may cause protein-binding site displacement. Furosemide has been shown to inhibit the protein binding of T4 to TBG and albumin, causing an increase free T4 fraction in serum. Furosemide competes for T4-binding sites on TBG, prealbumin, and albumin, so that a single high dose can acutely lower the total T4 level. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total and free T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. Closely monitor thyroid hormone parameters.


Table name:
Benzodiazepines
Clinical Impact:
There have been a number of reports regarding coma and death associated with the misuse and abuse of the combination of buprenorphine and benzodiazepines. In many, but not all of these cases, buprenorphine was misused by self-injection of crushed buprenorphine tablets. Preclinical studies have shown that the combination of benzodiazepines and buprenorphine altered the usual ceiling effect on buprenorphine-induced respiratory depression, making the respiratory effects of buprenorphine appear similar to those of full opioid agonists.
Intervention:
Closely monitor patients with concurrent use of buprenorphine and benzodiazepines. Warn patients that it is extremely dangerous to self-administer benzodiazepines while taking buprenorphine, and warn patients to use benzodiazepines concurrently with buprenorphine only as directed by their healthcare provider.
Non-Benzodiazepine Central Nervous System (CNS) Depressants
Clinical Impact:
Due to additive pharmacologic effects, the concomitant use of non-benzodiazepine CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:
Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.2, 5.3)].
Examples:
Alcohol, non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and other opioids.
Inhibitors of CYP3A4
Clinical Impact:
The concomitant use of buprenorphine and CYP3A4 inhibitors can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of buprenorphine is achieved.
 
After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the buprenorphine plasma concentration will decrease [see Clinical Pharmacology (12.3)], potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to buprenorphine.
Intervention:
If concomitant use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals.
 
If a CYP3A4 inhibitor is discontinued, consider increasing the buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
Examples:
Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)
CYP3A4 Inducers
Clinical Impact:
The concomitant use of buprenorphine and CYP3A4 inducers can decrease the plasma concentration of buprenorphine [see Clinical Pharmacology (12.3)], potentially resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine.
 
After stopping a CYP3A4 inducer, as the effects of the inducer decline, the buprenorphine plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both therapeutic effects and adverse reactions and may cause serious respiratory depression.
Intervention:
If concomitant use is necessary, consider increasing the buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider buprenorphine dosage reduction and monitor for signs of respiratory depression.
Examples:
Rifampin, carbamazepine, phenytoin
Antiretrovirals: Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Clinical Impact:
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are metabolized principally by CYP3A4. Efavirenz, nevirapine, and etravirine are known CYP3A inducers, whereas delaviridine is a CYP3A inhibitor. Significant pharmacokinetic interactions between NNRTIs (e.g., efavirenz and delavirdine) and buprenorphine have been shown in clinical studies, but these pharmacokinetic interactions did not result in any significant pharmacodynamic effects.
Intervention:
Patients who are on chronic buprenorphine treatment should have their dose monitored if NNRTIs are added to their treatment regimen.
Examples:
efavirenz, nevirapine, etravirine, delavirdine
Antiretrovirals: Protease inhibitors (PIs)
Clinical Impact:
Studies have shown some antiretroviral protease inhibitors (PIs) with CYP3A4 inhibitory activity (nelfinavir, lopinavir/ritonavir, ritonavir) have little effect on buprenorphine pharmacokinetic and no significant pharmacodynamic effects. Other PIs with CYP3A4 inhibitory activity (atazanavir and atazanavir/ritonavir) resulted in elevated levels of buprenorphine and norbuprenorphine, and patients in one study reported increased sedation. Symptoms of opioid excess have been found in postmarketing reports of patients receiving buprenorphine and atazanavir with and without ritonavir concomitantly.
Intervention:
Monitor patients taking buprenorphine and atazanavir with and without ritonavir, and reduce dose of buprenorphine if warranted.
Examples:
atazanavir, ritonavir
Antiretrovirals: Nucleoside reverse transcriptase inhibitors (NRTIs)
Clinical Impact:
Nucleoside reverse transcriptase inhibitors (NRTIs) do not appear to induce or inhibit the P450 enzyme pathway, thus no interactions with buprenorphine are expected.
Intervention:
None
Serotonergic Drugs
Clinical Impact:
The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention:
If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue buprenorphine if serotonin syndrome is suspected.
Examples:
Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:
MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma).
Intervention:
The use of buprenorphine is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples:
phenelzine, tranylcypromine, linezolid
Muscle Relaxants
Clinical Impact:
Buprenorphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:
Monitor patients receiving muscle relaxants and buprenorphine for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of buprenorphine and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact:
Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:
Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:
The concomitant use of anticholinergic drugs may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:
Monitor patients for signs of urinary retention or reduced gastric motility when buprenorphine is used concomitantly with anticholinergic drugs.


Table name:
Table 4: Clinically Relevant Interactions Affecting Omeprazole When Co-Administered with Other Drugs
CYP2C19 or CYP3A4 Inducers
Clinical Impact:
Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology ( 12.3)].
Intervention:
St. John’s Wort, rifampin: Avoid concomitant use with omeprazole [see Warnings and Precautions ( 5.9)].
Ritonavir-containing products: see prescribing information for specific drugs.
CYP2C19 or CYP3A4 Inhibitors
Clinical Impact:
Increased exposure of omeprazole [see Clinical Pharmacology ( 12.3)].
Intervention:
Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered.
 
See prescribing information for voriconazole.


Table name:
Table 7: Effect of Other Drugs on Voriconazole Pharmacokinetics
[see Clinical Pharmacology (12.3) ]
Drug/Drug Class
(Mechanism of
Interaction by the Drug)
Voriconazole Plasma
Exposure
(Cmax and AUCτ after
200 mg every 12h)
Recommendations for Voriconazole
Dosage Adjustment/Comments
Rifampin* and Rifabutin*
(CYP450 Induction)
Significantly Reduced Contraindicated
Efavirenz (400 mg daily)**
(CYP450 Induction)
Efavirenz (300 mg daily)** (CYP450 Induction)
Significantly Reduced Contraindicated
High-dose Ritonavir
(400 mg every 12h)**
(CYP450 Induction)
 
Low-dose Ritonavir
(100 mg every 12h)**
(CYP450 Induction)
Significantly Reduced
  
  
 
Reduced
Contraindicated
  
  
 
Coadministration of voriconazole and low-dose ritonavir (100 mg every 12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Carbamazepine
(CYP450 Induction)
Not Studied  In Vivo  or  In Vitro , but Likely
 to Result in Significant Reduction
Contraindicated
Long Acting Barbiturates
(CYP450 Induction)
Not Studied  In Vivo  or  In Vitro , but Likely
 to Result in Significant Reduction
Contraindicated
Phenytoin*
(CYP450 Induction)
Significantly Reduced Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV every 12h or from 200 mg to 400 mg orally every 12h (100 mg to 200 mg orally every 12h in patients weighing less than 40 kg)
St. John’s Wort
(CYP450 inducer; P-gp inducer)
Significantly Reduced Contraindicated
Oral Contraceptives**
containing ethinyl estradiol and norethindrone
(CYP2C19 Inhibition)
Increased Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole**
(CYP2C9, CYP2C19 and
CYP3A4 Inhibition)
Significantly Increased Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole.
Other HIV Protease
Inhibitors
(CYP3A4 Inhibition)
In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure
 
In Vitro
Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)
No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir
  
  
Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIs***
(CYP3A4 Inhibition or CYP450 Induction)
In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure)
 
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure)
Frequent monitoring for adverse events and toxicity related to voriconazole
   
  
 
Careful assessment of voriconazole effectiveness
Everolimus
(CYP3A4 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Concomitant administration of voriconazole and everolimus is not recommended.
*      Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg every 12h voriconazole to healthy subjects **    Results based on in vivo clinical study following repeat oral dosing with 400 mg every 12h for 1 day, then 200 mg every 12h for at least 2 days voriconazole to healthy subjects *** Non-Nucleoside Reverse Transcriptase Inhibitors


Table name:
Drugs That Interfere with Hemostasis
Clinical Impact: • Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of naproxen or naproxen sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: Concomitant use of naproxen or naproxen sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen or naproxen sodium is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE-inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: • During concomitant use of naproxen or naproxen sodium and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of naproxen or naproxen sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen or naproxen sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact: The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of naproxen or naproxen sodium and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen or naproxen sodium and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of naproxen or naproxen sodium and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of naproxen or naproxen sodium and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of naproxen or naproxen sodium and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of naproxen or naproxen sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of naproxen or naproxen sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact: Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention: Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen or naproxen sodium is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed release tablets are not recommended.
Cholestyramine
Clinical Impact: Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention: Concomitant administration of cholestyramine with naproxen or naproxen sodium is not recommended.
Probenecid
Clinical Impact: Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention: Patients simultaneously receiving naproxen or naproxen sodium and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact: Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention: Patients simultaneously receiving naproxen or naproxen sodium and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.


Table name:
Inhibitors of CYP3A4 and CYP2D6
Clinical Impact: The concomitant use of oxycodone hydrochloride tablets and CYP3A4 inhibitors can increase the plasma concentration of oxycodone, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of oxycodone hydrochloride tablets and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of oxycodone is achieved [see Warnings and Precautions (5.4)]. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the oxycodone plasma concentration will decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to oxycodone.
Intervention: If concomitant use is necessary, consider dosage reduction of oxycodone hydrochloride tablets until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the oxycodone hydrochloride tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir).
CYP3A4 Inducers
Clinical Impact: The concomitant use of oxycodone hydrochloride tablets and CYP3A4 inducers can decrease the plasma concentration of oxycodone [see Clinical Pharmacology (12.3)] , resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to oxycodone [see Warnings and Precautions (5.12)]. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the oxycodone plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.
Intervention: If concomitant use is necessary, consider increasing the oxycodone hydrochloride tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider oxycodone hydrochloride tablets dosage reduction and monitor for signs of respiratory depression.
Examples: Rifampin, carbamazepine, phenytoin
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.5)].
Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Adverse Reactions (6.2)].
Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue oxycodone hydrochloride tablets if serotonin syndrome is suspected.
Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)].
Intervention: The use of oxycodone hydrochloride tablets is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
Examples: phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist Opioid Analgesics
Clinical Impact: May reduce the analgesic effect of oxycodone hydrochloride tablets and/or may precipitate withdrawal symptoms.
Intervention: Avoid concomitant use
Examples: Butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact: Oxycodone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of oxycodone hydrochloride tablets and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention: Monitor patients for signs of dismissed diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact: The concomitant risk of anticholinergic drugs may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when oxycodone hydrochloride tablets are used concurrently with anticholinergic drugs.


Table name: When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
Table 7: Effect of Voriconazole on Pharmacokinetics of Other Drugs [see CLINICAL PHARMACOLOGY (12.3)]
       *Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects
     **Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects
   ***Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for 4 days voriconazole to subjects receiving a methadone maintenance dose (30 to 100 mg q24h)
  ****Non-Steroidal Anti-Inflammatory Drug
*****Non-Nucleoside Reverse Transcriptase Inhibitors
Drug/Drug Class (Mechanism of Interaction by Voriconazole) Drug Plasma Exposure
(Cmax and AUCτ)
Recommendations for Drug Dosage Adjustment/Comments
Sirolimus*
(CYP3A4 Inhibition)
Significantly Increased Contraindicated
Rifabutin*
(CYP3A4 Inhibition)
Significantly Increased Contraindicated
Efavirenz (400 mg q 24h)**
(CYP3A4 Inhibition)
 
Significantly Increased Contraindicated
Efavirenz (300 mg q 24h) **
(CYP3A4 Inhibition)
Slight decrease in AUCt
 
High-dose Ritonavir
(400 mg q12h)**
(CYP3A4 Inhibition)
No Significant Effect of Voriconazole on Contraindicated because of significant reduction of voriconazole Cmax and AUCτ
Ritonavir Cmax or AUCτ
Low-dose Ritonavir
(100 mg q12h)**
Slight Decrease in Ritonavir Cmax and AUCτ Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole Cmax and AUCτ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids
(CYP450 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Contraindicated
Cyclosporine*
(CYP3A4 Inhibition)
AUCτ Significantly Increased; No Significant Effect on Cmax When initiating therapy with voriconazole in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When voriconazole is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
Methadone***
(CYP3A4 Inhibition)
Increased Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed.
Fentanyl
(CYP3A4 Inhibition)
Increased Reduction in the dose of fentanyl and other longacting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see DRUG INTERACTIONS (7)].
Alfentanil
(CYP3A4 Inhibition)
Significantly Increased Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with voriconazole. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [see DRUG INTERACTIONS (7)].
Oxycodone
(CYP3A4 Inhibition)
Significantly Increased Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see DRUG INTERACTIONS (7)].
NSAIDs****
including ibuprofen and diclofenac
(CYP2C9 Inhibition)
Increased Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed. [see DRUG INTERACTIONS (7)].
Tacrolimus* (CYP3A4 Inhibition) Significantly Increased When initiating therapy with voriconazole in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazole is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin* (CYP2C9 Inhibition) Significantly Increased Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone
(CYP3A4 Inhibition)**
Increased Monitoring for adverse events related to oral contraceptives is recommended during coadministration.
Warfarin* (CYP2C9 Inhibition) Prothrombin Time Significantly Increased Monitor PT or other suitable anticoagulation tests. Adjustment of warfarin dosage may be needed.
Omeprazole* (CYP2C19/3A4 Inhibition) Significantly Increased When initiating therapy with voriconazole in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors (CYP3A4 Inhibition) In Vivo Studies Showed No Significant Effects on Indinavir Exposure No dosage adjustment for indinavir when coadministered with voriconazole
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors
Other NNRTIs***** (CYP3A4 Inhibition) A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to NNRTI
Benzodiazepines (CYP3A4 Inhibition) In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.
HMG-CoA Reductase Inhibitors (Statins)
(CYP3A4 Inhibition)
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition) In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics
(CYP2C9 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed.
Everolimus (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Concomitant administration of voriconazole and everolimus is not recommended.


Table name:
Table II. Clinically significant drug interactions with theophylline.Refer to PRECAUTIONS, Drug Interactions for further information regarding table.
Drug Type of Interaction EffectAverage effect on steady-state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.
Adenosine Theophylline blocks adenosine receptors. Higher doses of adenosine may be required to achieve desired effect.
Alcohol A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours. 30% increase
Allopurinol Decreases theophylline clearance at allopurinol doses ≥600 mg/day. 25% increase
Aminoglutethimide Increases theophylline clearance by induction of microsomal enzyme activity. 25% decrease
Carbamazepine Similar to aminoglutethimide. 30% decrease
Cimetidine Decreases theophylline clearance by inhibiting cytochrome P450 1A2. 70% increase
Ciprofloxacin Similar to cimetidine. 40% increase
Clarithromycin Similar to erythromycin. 25% increase
Diazepam Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram Decreases theophylline clearance by inhibiting hydroxylation and demethylation. 50% increase
Enoxacin Similar to cimetidine. 300% increase
Ephedrine Synergistic CNS effects Increased frequency of nausea, nervousness, and insomnia.
Erythromycin Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3. 35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown. 30% increase
Flurazepam Similar to diazepam. Similar to diazepam.
Fluvoxamine Similar to cimetidine. Similar to cimetidine.
Halothane Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines. Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-A Decreases theophylline clearance. 100% increase
Isoproterenol (IV) Increase theophylline clearance. 20% increase
Ketamine Pharmacologic May lower theophylline seizure threshold.
Lithium Theophylline increases renal lithium clearance. Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam Similar to diazepam. Similar to diazepam.
Methotrexate (MTX) Decreases theophylline clearance. 20% increase after low dose MTX, higher dose MTX may have a greater effect.
Mexiletine Similar to disulfiram. 80% increase
Midazolam Similar to diazepam. Similar to diazepam.
Moricizine Increases theophylline clearance. 25% decrease
Pancuronium Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition. Larger dose of pancuronium may be required to achieve neuromuscular blockade.
Pentoxifylline Decreases theophylline clearance. 30% increase
Phenobarbital (PB) Similar to aminoglutethimide. 25% decrease after two weeks of concurrent PB.
Phenytoin Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption. Serum theophylline and phenytoin concentrations decrease about 40%.
Propafenone Decreases theophylline clearance and pharmacologic interaction. 40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Propranolol Similar to cimetidine and pharmacologic interaction. 100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Rifampin Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity. 20 to 40% decrease
Sulfinpyrazone Increase theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline. 20% increase
Tacrine Similar to cimetidine, also increases renal clearance of theophylline. 90% increase
Thiabendazole Decreases theophylline clearance. 190% increase
Ticlopidine Decreases theophylline clearance. 60% increase
Troleandomycin Similar to erythromycin. 33 to 100% increase depending on troleandomycin dose.
Verapamil Similar to disulfiram. 20% increase


Table name:
Drug Effect
Phenylephrine with prior administration
of monoamine oxidase inhibitors (MAOI).
Cardiac pressor response potentiated.
May cause acute hypertensive crisis.
Phenylephrine with tricyclic
antidepressants.
Pressor response increased.
Phenylephrine with ergot alkaloids. Excessive rise in blood pressure.
Phenylephrine with bronchodilator
sympathomimetic agents and with
epinephrine or other sympathomimetics.
Tachycardia or other arrhythmias may occur.
Phenylephrine with prior administration
of propranolol or other β-adrenergic
blockers.
Cardiostimulating effects blocked.
Phenylephrine with atropine sulfate. Reflex bradycardia blocked; pressor
response enhanced.
Phenylephrine with prior administration
of phentolamine or other α-adrenergic blockers.
Pressor response decreased.
Phenylephrine with diet preparations, such
as amphetamines or phenylpropanolamine.
Synergistic adrenergic response.


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on
Concentration of Lamotrigine or Concomitant Drug
Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine Decreased lamotrigine concentrations approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? carbamazepine epoxide May increase carbamazepine epoxide levels.
 Lopinavir/ritonavir ↓ lamotrigine Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir ↓ lamotrigine Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine
Increased lamotrigine concentrations slightly more than 2-fold.
? valproate There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Grapefruit juice Avoid grapefruit juice


Table name:
Table 9. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class:
Drug Name
Effect on Concentration of Lopinavir or Concomitant Drug Clinical Comments
HIV-1 Antiviral Agents
Non-nucleoside Reverse Transcriptase Inhibitors:
efavirenz*,
nevirapine*
↓ lopinavir KALETRA dose increase is recommended in all patients [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
Increasing the dose of KALETRA tablets to 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) twice daily co-administered with efavirenz resulted in similar lopinavir concentrations compared to KALETRA tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz.
Increasing the dose of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice daily co-administered with efavirenz resulted in significantly higher lopinavir plasma concentrations compared to KALETRA tablets 400/100 mg twice daily without efavirenz.
KALETRA should not be administered once daily in combination with efavirenz or nevirapine
[see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
Non-nucleoside Reverse Transcriptase Inhibitor:
delavirdine
↑ lopinavir Appropriate doses of the combination with respect to safety and efficacy have not been established.
Nucleoside Reverse Transcriptase Inhibitor:
didanosine
  KALETRA tablets can be administered simultaneously with didanosine without food.
For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food).
Nucleoside Reverse Transcriptase Inhibitor:
tenofovir
↑ tenofovir KALETRA increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir.
Nucleoside Reverse Transcriptase Inhibitor:
abacavir
zidovudine
↓ abacavir
↓ zidovudine
KALETRA induces glucuronidation; therefore, KALETRA has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown.
HIV-1 Protease Inhibitor:
amprenavir*
↑ amprenavir
↓ lopinavir
KALETRA should not be administered once daily in combination with amprenavir
[see Dosage and Administration (2.1)].
HIV-1 Protease Inhibitor:
fosamprenavir/ritonavir
↓ amprenavir
↓ lopinavir
An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor:
indinavir*
↑ indinavir Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily [see Clinical Pharmacology (12.3)]. KALETRA once daily has not been studied in combination with indinavir.
HIV-1 Protease Inhibitor:
nelfinavir*
↑ nelfinavir
↑ M8 metabolite of nelfinavir
↓ lopinavir
KALETRA should not be administered once daily in combination with nelfinavir
[see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].

HIV-1 Protease Inhibitor:
ritonavir*
↑ lopinavir Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor:
saquinavir*
↑ saquinavir The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily.
KALETRA once daily has not been studied in combination with saquinavir.
HIV-1 Protease Inhibitor:
tipranavir
↓ lopinavir AUC and Cmin KALETRA should not be administered with tipranavir (500 mg twice daily) co-administered with ritonavir (200 mg twice daily).
HIV CCR5 – Antagonist:
maraviroc
↑ maraviroc Concurrent administration of maraviroc with KALETRA will increase plasma levels of maraviroc. When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for Selzentry® (maraviroc).
Other Agents
Antiarrhythmics:
amiodarone,
bepridil,
lidocaine (systemic),
quinidine
↑ antiarrhythmics Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA.
Anticancer Agents:
vincristine,
vinblastine,
dasatinib,
nilotinib
↑ anticancer agents Concentrations of these drugs may be increased when co-administered with KALETRA resulting in the potential for increased adverse events usually associated with these anticancer agents.
For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when KALETRA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor.
A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as KALETRA. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions.
Anticoagulant:
warfarin
  Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants:
carbamazepine,
phenobarbital,
phenytoin
↓ lopinavir
↓ phenytoin
KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution.
KALETRA should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin.

In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA.
Antidepressant:
bupropion
↓ bupropion
↓ active metabolite,
hydroxybupropion
Concurrent administration of bupropion with KALETRA may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion.
Antidepressant:
trazodone
↑ trazodone Concomitant use of trazodone and KALETRA may increase concentrations of trazodone. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered.
Anti-infective:
clarithromycin
↑ clarithromycin For patients with renal impairment, the following dosage adjustments should be considered:
  • For patients with CLCR 30 to 60 mL/min the dose
    of clarithromycin should be reduced by 50%.
  • For patients with CLCR < 30 mL/min the dose
    of clarithromycin should be decreased by 75%.

No dose adjustment for patients with normal renal function is necessary.
Antifungals:
ketoconazole*,
itraconazole,
voriconazole
↑ ketoconazole
↑ itraconazole
↓ voriconazole
High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended.
Co-administration of voriconazole with KALETRA has not been studied. However, a study has been shown that administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%; therefore, co-administration of KALETRA and voriconazole may result in decreased voriconazole concentrations and the potential for decreased voriconazole effectiveness and should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Otherwise, alternative antifungal therapies should be considered in these patients.
Anti-gout:
colchicine
↑ colchicine Patients with renal or hepatic impairment should not be given colchicine with KALETRA.

Treatment of gout flares-co-administration of colchicine in patients on KALETRA:

0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days.

Prophylaxis of gout flares-co-administration of colchicine in patients on KALETRA:

If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.

If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.

Treatment of familial Mediterranean fever (FMF)-co-administration of colchicine in patients on KALETRA:

Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Antimycobacterial:
rifabutin*
↑ rifabutin and rifabutin metabolite Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary.
Antimycobacterial:
rifampin
↓ lopinavir May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents. A study evaluated combination of rifampin 600 mg once daily, with KALETRA 800/200 mg twice daily or KALETRA 400/100 mg + ritonavir 300 mg twice daily. Pharmacokinetic and safety results from this study do not allow for a dose recommendation. Nine subjects (28%) experienced a ≥ grade 2 increase in ALT/AST, of which seven (21%) prematurely discontinued study per protocol. Based on the study design, it is not possible to determine whether the frequency or magnitude of the ALT/AST elevations observed is higher than what would be seen with rifampin alone [see Clinical Pharmacology (12.3) for magnitude of interaction].
Antiparasitic:
atovaquone
↓ atovaquone Clinical significance is unknown; however, increase in atovaquone doses may be needed.
Benzodiazepines: parenterally administered midazolam ↑ midazolam Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, KALETRA should not be given with orally administered midazolam [see Contraindications (4)]. If KALETRA is co-administered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.
Calcium Channel Blockers:
dihydropyridine,
felodipine,
nifedipine,
nicardipine
↑ dihydropyridine calcium channel blockers Caution is warranted and clinical monitoring of patients is recommended.
Contraceptive:
ethinyl estradiol*
↓ ethinyl estradiol Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended.
Corticosteroid:
dexamethasone

↓ lopinavir Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly.


disulfiram/metronidazole   KALETRA oral solution contains alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).
Endothelin Receptor Antagonists:
bosentan
↑ bosentan Co-administration of bosentan in patients on KALETRA:

In patients who have been receiving KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

Co-administration of KALETRA in patients on bosentan:

Discontinue use of bosentan at least 36 hours prior to initiation of KALETRA.

After at least 10 days following the initiation of KALETRA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
HMG-CoA Reductase Inhibitors:
atorvastatin
rosuvastatin
↑ atorvastatin
↑ rosuvastatin
Use atorvastatin with caution and at the lowest necessary dose. Titrate rosuvastatin dose carefully and use the lowest necessary dose; do not exceed rosuvastatin 10 mg/day. See Drugs with No Observed or Predicted Interactions with KALETRA (7.4) and Clinical Pharmacology (12.3) for drug interaction data with other HMG-CoA reductase inhibitors.
Immunosuppressants:
cyclosporine,
tacrolimus,
rapamycin
↑ immunosuppressants Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA.
Inhaled Steroid:
fluticasone
↑ fluticasone Concomitant use of fluticasone propionate and KALETRA may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during post-marketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Co-administration of fluticasone propionate and KALETRA is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effect.
Long-acting beta-adrenoceptor Agonist:
salmeterol
↑ salmeterol Concurrent administration of salmeterol and KALETRA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Narcotic Analgesic:
methadone*
fentanyl
↓ methadone
↑ fentanyl
Dosage of methadone may need to be increased when co-administered with KALETRA.
Concentrations of fentanyl are expected to increase. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with KALETRA.
PDE5 inhibitors:
sildenafil,
tadalafil,
vardenafil
↑ sildenafil
↑ tadalafil
↑ vardenafil
Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs is expected to substantially increase their concentrations and may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection.

Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH):

Sildenafil (Revatio®) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with KALETRA [see Contraindications (4)].

The following dose adjustments are recommended for use of tadalafil (Adcirca®) with KALETRA:

Co-administration of ADCIRCA in patients on KALETRA:

In patients receiving KALETRA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Co-administration of KALETRA in patients on ADCIRCA:

Avoid use of ADCIRCA during the initiation of KALETRA. Stop ADCIRCA at least 24 hours prior to starting KALETRA. After at least one week following the initiation of KALETRA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Use of PDE5 inhibitors for erectile dysfunction:

It is recommended not to exceed the following doses:
  • Sildenafil: 25 mg every 48 hours
  • Tadalafil: 10 mg every 72 hours
  • Vardenafil: 2.5 mg every 72 hours

Use with increased monitoring for adverse events.
*   see Clinical Pharmacology (12.3) for magnitude of interaction.


Table name:
Concomitant Drug Name or Drug Class Clinical Rationale Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)] . With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)] .
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin) The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)] . With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)] .
Antihypertensive Drugs Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.7)] .
Benzodiazepines (e.g., lorazepam) The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.7)]. Monitor sedation and blood pressure. Adjust dose accordingly.


Table name:
Digoxin concentrations increased greater than 50%
     Digoxin Serum     
Concentration
Increase
     Digoxin AUC     
Increase
Recommendations
Quinidine NA 54-83% Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring.
Ritonavir NA 86%
Digoxin concentrations increased less than 50%
Amiodarone 17% 40% Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring.
Propafenone 28% 29%
Quinine NA 34-38%
Spironolactone      NA 44%
Verapamil NA 24%


Table name:
Drug Interactions Associated With Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) Do not exceed 40 mg atorvastatin daily


Table name:
Interacting Drug Interaction
Theophylline Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin Monitor phenytoin level (7)
Methotrexate Monitor for methotrexate toxicity (7)
Cyclosporine May increase serum creatinine. Monitor serum creatinine (7)


Table name:
Drugs That Interfere with Hemostasis
Clinical Impact: Oxaprozin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of oxaprozin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case- control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of oxaprozin with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2) ].
Intervention: Concomitant use of oxaprozin and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11) ]. Oxaprozin is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta- blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: During concomitant use of oxaprozin and ACE-inhibitors, ARBs, or beta- blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of oxaprozin and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6) ].

When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of oxaprozin with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6) ].
Digoxin
Clinical Impact: The concomitant use of oxaprozin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of oxaprozin and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of oxaprozin and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction) because NSAID administration may result in increased plasma levels of methotrexate, especially in patients receiving high doses of methotrexate.
Intervention: During concomitant use of oxaprozin and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of oxaprozin and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of oxaprozin and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of oxaprozin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention: The concomitant use of oxaprozin with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of oxaprozin and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of oxaprozin and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.

Corticosteroids
Clinical Impact: Concomitant use of corticosteroids with oxaprozin may increase the risk of GI ulceration or bleeding.
Intervention: Monitor patients with concomitant use of oxaprozin with corticosteroids for signs of bleeding [see Warnings and Precautions (5.2)].
Glyburide
Clinical Impact: While oxaprozin does alter the pharmacokinetics of glyburide, co-administration of oxaprozin to type II non-insulin dependent diabetic patients did not affect the area under the glucose concentration curve nor the magnitude or duration of control.
Intervention: During concomitant use of oxaprozin and glyburide, monitor patient’s blood glucose in the beginning phase of cotherapy.


Table name:
Table 18. Summary of Effect of Co-administered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Co-administered
Drug
Dosing Schedule Effect on Active Moiety
(Risperidone + 9-
Hydroxy-Risperidone
(RatioChange relative to reference)
Risperidone Dose
Recommendation
Co-administered Drug Risperidone AUC Cmax
Enzyme
(CYP 2D6)
Inhibitors
Fluoxetine 20 mg/day 2 mg or 3 mg
twice daily
1.4 1.5 Re-evaluate
dosing. Do not
exceed 8 mg/day
Paroxetine 10 mg/day 4 mg/day 1.3 - Re-evaluate
dosing. Do not
exceed 8 mg/day
20 mg/day 4 mg/day 1.6 -
40 mg/day 4 mg/day 1.8 -
Enzyme
(CYP3A/PgP
inducers)
Inducers
Carbamazepine 573 mg/day ± 168
mg/day
3 mg twice
daily
0.51 0.55 Titrate dose
upwards. Do not
exceed twice the
patient’s usual
dose
Enzyme
(CYP3A)
Inhibitors
Ranitidine 150 mg twice
daily
1 mg single
dose
1.2 1.4 Dose adjustment
not needed
Cimetidine 400 mg twice
daily
1 mg single
dose
1.1 1.3 Dose adjustment
not needed
Erythromycin 500 mg 4 times
daily
1 mg single
dose
1.1 0.94 Dose adjustment
not needed
Other Drugs
Amitriptyline 50 mg twice
daily
3 mg twice
daily
1.2 1.1 Dose adjustment
not needed


Table name:
Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s) Recommendation Comments
Tizanidine Contraindicated Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)].
Theophylline Avoid Use (Plasma Exposure Likely to be Increased and Prolonged) Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate[see Warnings and Precautions (5.6).]
Drugs Known to Prolong QT Interval Avoid Use Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.10) and Use in Specific Populations (8.5)].
Oral antidiabetic drugs Use with caution Glucose-lowering effect potentiated Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs. [see Adverse Reactions (6.1).]
Phenytoin Use with caution Altered serum levels of phenytoin (increased and decreased) To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after coadministration of ciprofloxacin with phenytoin.
Cyclosporine Use with caution (transient elevations in serum creatinine) Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs Use with caution (Increase in anticoagulant effect) The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole Use with caution Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after coadministration with ciprofloxacin [see Warnings and Precautions (5.15)].
Clozapine Use with caution Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs Use with caution Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil Use with caution 2-fold increase in exposure Monitor for sildenafil toxicity (see Pharmacokinetics -(12.3)-].
Duloxetine Avoid Use 5-fold increase in duloxetine exposure If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products) Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2)]. Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels) Potentiation of ciprofloxacin toxicity may occur.


Table name:
Interacting Agents Prescribing
Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol
Contraindicated with simvastatin
Verapamil, diltiazem
Do not exceed 10 mg
simvastatin daily
Amiodarone, amlodipine, ranolazine
Do not exceed 20 mg
simvastatin daily
Grapefruit juice
Avoid large quantities of
grapefruit juice (>1 quart daily)


Table name:
Table 5. Established and Other Potentially Significant Drug Interactions
↓= Decreased (induces lamotrigine glucuronidation).
↑= Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral
contraceptive preparations
containing 30 mcg ethinylestradiol
and 150 mcg levonorgestrel
↓ lamotrigine Decreased lamotrigine
concentrations approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel
component by 19%.
Carbamazepine and
Carbamazepine epoxide
↓ lamotrigine Addition of carbamazepine decreases
lamotrigine concentration
approximately 40%.
? carbamazepine
epoxide.
May increase carbamazepine
Epoxide levels.
Lopinavir/ritonavir ↓ lamotrigine Decreased lamotrigine concentration
approximately 50%.
Atazanavir/ritonavir ↓ lamotrigine Decreased lamotrigine AUC
approximately 32%.
Phenobarbital/primidone ↓ lamotrigine Decreased lamotrigine concentration
approximately 40%.
Phenytoin ↓ lamotrigine Decreased lamotrigine concentration
approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC
approximately 40%.
Valproate ↑ lamotrigine Increased lamotrigine concentrations
slightly more than 2-fold.
? valproate There are conflicting study results
regarding effect of lamotrigine on
valproate concentrations: 1) a mean 25%
decrease in valproate concentrations in
healthy volunteers, 2) no change in
valproate concentrations in controlled
clinical trials in patients with epilepsy.


Table name:
Figure 2: Effect of venlafaxine on the pharmacokinetics interacting drugs and their active metabolites.


Table name:
 Interacting  Agents 
 Prescribing  Recommendations 
 Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, 
posaconazole, voriconazole, erythromycin, clarithromycin, 
telithromycin, HIV protease inhibitors, boceprevir, telaprevir, 
nefazodone, cobicistatcontaining products), gemfibrozil, 
cyclosporine, danazol 
  Contraindicated with simvastatin 
 Verapamil, diltiazem, dronedarone
 Do not exceed 10 mg simvastatin daily 
 Amiodarone, amlodipine, ranolazine
 Do not exceed 20 mg simvastatin daily 
 Lomitapide
 For patients with HoFH, do not exceed 
20 mg simvastatin dailyFor patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
 Grapefruit juice 
 Avoid grapefruit juice  


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 45.1, 7.1, 7.2, 7.3, 12.3)
   Interacting Agents    Prescribing Recommendations
   Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol
   Contraindicated with simvastatin
   Verapamil, diltiazem, dronedarone
   Do not exceed 10 mg simvastatin daily
   Amiodarone, amlodipine, ranolazine
   Do not exceed 20 mg simvastatin daily
   Grapefruit juice
   Avoid grapefruit juice


Table name:
Interacting Drug Interaction
Theophylline Serious and fatal reactions. Avoid concomitant use. Monitor serum level ( 7)
Warfarin Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding ( 7)
Antidiabetic agents Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose ( 7)
Phenytoin Monitor phenytoin level ( 7)
Methotrexate Monitor for methotrexate toxicity ( 7)
Cyclosporine May increase serum creatinine. Monitor serum creatinine ( 7)
Multivalent cation-containing products including antacids, metal cations or didanosine Decreased ciprofloxacin tablets absorption. Take 2 hours before or 6 hours after ciprofloxacin tablets ( 7)


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
 Concomitant Drug  Effect on Concentration of Lamotrigine or Concomitant Drug  Clinical Comment
 Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel  ↓ lamotrigine  Decreased lamotrigine levels approximately 50%.
   ↓ levonorgestrel  Decrease in levonorgestrel component by 19%.
 Carbamazepine (CBZ) and CBZ epoxide  ↓ lamotrigine  Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
   ? CBZ epoxide  May increase CBZ epoxide levels
 Phenobarbital/Primidone  ↓ lamotrigine  Decreased lamotrigine concentration approximately 40%.
 Phenytoin (PHT)  ↓ lamotrigine  Decreased lamotrigine concentration approximately 40%.
 Rifampin  ↓ lamotrigine  Decreased lamotrigine AUC approximately 40%.
 Valproate  ↑ lamotrigine  Increased lamotrigine concentrations slightly more than 2-fold.
   ? valproate  Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
Table 2Clinically Significant Drug Interactions with Indomethacin Drugs That Interfere with Hemostasis
Clinical  Impact
Indomethacin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant uses of indomethacin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. 
Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. 
Intervention
Monitor patients with concomitant use of indomethacin capsules with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see  Warnings  and  Precautions  ( 5 . 11)].
Aspirin

Clinical  Impact

Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see  Warnings  and  Precautions  ( 5 . 2)]. 
Intervention

Concomitant use of indomethacin capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see  Warnings  and  Precautions  ( 5 . 11)]. Indomethacin capsules are not a substitute for low dose aspirin for cardiovascular protection.
ACE  Inhibitors Angiotensin  Receptor  Blockers and  Beta - Blockers

Clinical  Impact

NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). 
In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. 
Intervention :
During concomitant use of indomethacin capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. 
During concomitant use of Indomethacin capsules and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see  Warnings  and  Precautions  ( 5 . 6)].
When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. 
Diuretics

Clinical  Impact

Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. 
It has been reported that the addition of triamterene to a maintenance schedule of Indomethacin capsules resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin capsules and triamterene should not be administered together. 
Both Indomethacin capsules and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin capsules and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently. 
Intervention

Indomethacin and triamterene should not be administered together. During concomitant use of indomethacin capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects. 
Be aware that indomethacin and potassium-sparing diuretics may both be associated with increased serum potassium levels [see  Warnings  and  Precautions  ( 5 . 6)]. 
Digoxin

Clinical  Impact

The concomitant use of indomethacin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. 
Intervention

During concomitant use of indomethacin capsules and digoxin, monitor serum digoxin levels. 
Lithium

Clinical  Impact

NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearanceThe mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention

During concomitant use of indomethacin capsules and lithium, monitor patients for signs of lithium toxicity. 
Methotrexate

Clinical  Impact

Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). 
Intervention

During concomitant use of indomethacin capsules and methotrexate, monitor patients for methotrexate toxicity. 
Cyclosporine

Clinical  Impact

Concomitant use of indomethacin capsules and cyclosporine may increase cyclosporine’s nephrotoxicity. 
Intervention

During concomitant use of indomethacin capsules and cyclosporine, monitor patients for signs of worsening renal function. 
NSAIDs  and  Salicylates

Clinical  Impact

Concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see  Warnings  and  Precautions  ( 5 . 2 )]. 
Combined use with diflunisal may be particularly hazardous because diflunisal causes significantly higher plasma levels of indomethacin. [see Clinical  Pharmacology  ( 12 . 3)]. 
In some patients, combined use of indomethacin and diflunisal has been associated with fatal gastrointestinal hemorrhage. 
Intervention

The concomitant use of indomethacin with other NSAIDs or salicylates, especially diflunisal, is not recommended. 
Pemetrexed

Clinical  Impact

Concomitant use of indomethacin capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). 
Intervention

During concomitant use of indomethacin capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. 
NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. 
In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. 
Probenecid

Clinical  Impact

When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased. 
Intervention

During the concomitant use of indomethacin capsules and probenecid, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect. When increases in the dose of indomethacin are made, they should be made carefully and in small increments. 


Table name:
Drugs that Affect Renal
Function
A decline in GFR or tubular secretion, as from ACE inhibitors,
angiotensin receptor blockers, nonsteroidal anti-inflammatory
drugs [NSAIDS], COX-2 inhibitors may impair the excretion of
digoxin.
Antiarrthymics Dofetilide Concomitant administration with digoxin was associated with a higher rate of torsades de pointes
Sotalol Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
Dronedarone Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone Analog Teriparatide Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement Thyroid Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics Epinephrine
Norepinephrine
Dopamine
Can increase the risk of cardiac arrhythmias
Neuromuscular Blocking Agents Succinylcholine May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.
Supplements Calcium If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.
Hyperpolarization-activated cyclic nucleotide-gated channel blocker Ivabradine Can increase the risk of bradycardia.


Table name:
Antiretrovirals
        Clinical Impact: The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology (12.3)]. Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see Clinical Pharmacology (12.3)]. There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole.
        Intervention: Rilpivirine-containing products: Concomitant use with omeprazole is contraindicated [see Contraindications (4)].

Atazanavir: Avoid concomitant use with omeprazole. See prescribing information for atazanavir for dosing information.

Nelfinavir: Avoid concomitant use with omeprazole. See prescribing information for nelfinavir.

Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities.

Other antiretrovirals: See prescribing information for specific antiretroviral drugs.
Warfarin
Clinical Impact: Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
Intervention: Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range.
Methotrexate
Clinical Impact: Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions (5.11)].
Intervention: A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate.
CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam)
Clopidogrel
Clinical Impact: Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology (12.3)].

There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel.
Intervention: Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy [see Warnings and Precautions (5.6)].
Citalopram
Clinical Impact: Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology (12.3)].
Intervention: Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.
Cilostazol
Clinical Impact: Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology (12.3)].
Intervention: Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.
Phenytoin
Clinical Impact: Potential for increased exposure of phenytoin.
Intervention: Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin.
Diazepam
Clinical Impact: Increased exposure of diazepam [see Clinical Pharmacology (12.3)].
Intervention: Monitor patients for increased sedation and reduce the dose of diazepam as needed.
Digoxin
Clinical Impact: Potential for increased exposure of digoxin [see Clinical Pharmacology (12.3)].
Intervention: Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)
Clinical Impact: Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
     Intervention: Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF [see Clinical Pharmacology (12.3)].

See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact: Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated.
Amoxicillin also has drug interactions.
Intervention: See Contraindications, Warnings and Precautions in prescribing information for clarithromycin.

See Drug Interactions in prescribing information for amoxicillin.
Tacrolimus
Clinical Impact: Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.
Intervention: Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact: Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions (5.10), Clinical Pharmacology (12.2)].
  Intervention: Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
Interaction with Secretin Stimulation Test
Clinical Impact: Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention: Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology (12.2)].
False Positive Urine Tests for THC
Clinical Impact: There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.
Intervention: An alternative confirmatory method should be considered to verify positive results.
Other
Clinical Impact: There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram).
Intervention: Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
   Interacting Agents    Prescribing Recommendations
   Strong CYP3A4 inhibitors (e.g.,itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicstat-containing products), gemfibrozil, cyclosporine, danazol
   Contraindicated with simvastatin
   Verapamil, diltiazem, dronedarone
   Do not exceed 10 mg simvastatin daily
   Amiodarone, amlodipine, ranolazine
   Do not exceed 20 mg simvastatin daily
   Lomitapide     For patients with HoFH, do not exceed 20 mg simvastatin daily*
   Grapefruit juice
   Avoid grapefruit juice


Table name:
1A22C93A42C19
WarfarinWarfarinAlprazolamOmeprazole
Theophylline
Propranolol
Tizanidine


Table name:
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:
The concomitant use of SSRIs including sertraline hydrochloride and MAOIs increases the risk of serotonin syndrome.
Intervention:
Sertraline hydrochloride is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [See Dosage and Administration (2.5), Contraindications (4), Warnings and Precautions (5.2)].
Examples:
selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue
Pimozide
Clinical Impact:
Increased plasma concentrations of pimozide, a drug with a narrow therapeutic index, may increase the risk of QT prolongation and ventricular arrhythmias.
Intervention:
Concomitant use of pimozide and sertraline hydrochloride is contraindicated [See Contraindications (4)].
Other Serotonergic Drugs
Clinical Impact:
The concomitant use of serotonergic drugs with sertraline hydrochloride increases the risk of serotonin syndrome.
Intervention:
Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of sertraline hydrochloride and/or concomitant serotonergic drugs [See Warnings and Precautions (5.2)].
Examples:
other SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort
Drugs that Interfere with Hemostasis (antiplatelet agents and anticoagulants)
Clinical Impact:
The concurrent use of an antiplatelet agent or anticoagulant with sertraline hydrochloride may potentiate the risk of bleeding.
Intervention:
Inform patients of the increased risk of bleeding associated with the concomitant use of sertraline hydrochloride and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio [See Warnings and Precautions (5.3)].
Examples:
aspirin, clopidogrel, heparin, warfarin
Drugs Highly Bound to Plasma Protein
Clinical Impact:
Sertraline hydrochloride is highly bound to plasma protein. The concomitant use of sertraline hydrochloride with another drug that is highly bound to plasma protein may increase free concentrations of sertraline hydrochloride or other tightly-bound drugs in plasma [See Clinical Pharmacology (12.3)].
Intervention:
Monitor for adverse reactions and reduce dosage of sertraline hydrochloride or other protein-bound drugs as warranted.
Examples:
warfarin
Drugs Metabolized by CYP2D6
Clinical Impact:
Sertraline hydrochloride is a CYP2D6 inhibitor [See Clinical Pharmacology (12.3)]. The concomitant use of sertraline hydrochloride with a CYP2D6 substrate may increase the exposure of the CYP2D6 substrate.
Intervention:
Decrease the dosage of a CYP2D6 substrate if needed with concomitant sertraline hydrochloride use. Conversely, an increase in dosage of a CYP2D6 substrate may be needed if sertraline hydrochloride is discontinued.
Examples:
propafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, thoridazine, tolterodine, venlafaxine
Phenytoin
Clinical Impact:
Phenytoin is a narrow therapeutic index drug. sertraline hydrochloride may increase phenytoin concentrations.
Intervention:
Monitor phenytoin levels when initiating or titrating sertraline hydrochloride. Reduce phenytoin dosage if needed.
Examples:
phenytoin, fosphenytoin


Table name:
Benzodiazepines
Clinical Impact: There have been a number of reports regarding coma and death associated with the misuse and abuse of the combination of buprenorphine and benzodiazepines. In many, but not all of these cases, buprenorphine was misused by self-injection of crushed buprenorphine tablets. Preclinical studies have shown that the combination of benzodiazepines and buprenorphine altered the usual ceiling effect on buprenorphine-induced respiratory depression, making the respiratory effects of buprenorphine appear similar to those of full opioid agonists.
Intervention: Closely monitor patients with concurrent use of buprenorphine sublingual tablets and benzodiazepines. Warn patients that it is extremely dangerous to self-administer benzodiazepines while taking buprenorphine sublingual tablets, and warn patients to use benzodiazepines concurrently with buprenorphine sublingual tablets only as directed by their healthcare provider.
Non-Benzodiazepine Central Nervous System (CNS) Depressants
Clinical Impact: Due to additive pharmacologic effect, the concomitant use of non-benzodiazepine CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.2, 5.3)].
Examples: Alcohol, non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and other opioids.
Inhibitors of CYP3A4
Clinical Impact: The concomitant use of buprenorphine and CYP3A4 inhibitors can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of buprenorphine sublingual tablets is achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the buprenorphine plasma concentration will decrease [see Clinical Pharmacology (12.3)], potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to buprenorphine.
Intervention: If concomitant use is necessary, consider dosage reduction of buprenorphine sublingual tablets until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the buprenorphine sublingual tablet dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir)
CYP3A4 Inducers
Clinical Impact: The concomitant use of buprenorphine and CYP3A4 inducers can decrease the plasma concentration of buprenorphine [see Clinical Pharmacology (12.3)], potentially resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the buprenorphine plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both therapeutic effects and adverse reactions and may cause serious respiratory depression.
Intervention: If concomitant use is necessary, consider increasing the buprenorphine sublingual tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider buprenorphine sublingual tablets dosage reduction and monitor for signs of respiratory depression.
Examples: Rifampin, carbamazepine, phenytoin
Antiretrovirals: Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Clinical Impact: Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are metabolized principally by CYP3A4. Efavirenz, nevirapine, and etravirine are known CYP3A inducers, whereas delaviridine is a CYP3A inhibitor. Significant pharmacokinetic interactions between NNRTIs (e.g., efavirenz and delavirdine) and buprenorphine have been shown in clinical studies, but these pharmacokinetic interactions did not result in any significant pharmacodynamic effects.
Intervention: Patients who are on chronic buprenorphine sublingual tablets treatment should have their dose monitored if NNRTIs are added to their treatment regimen.
Examples: efavirenz, nevirapine, etravirine, delavirdine
Antiretrovirals: Protease inhibitors (PIs)
Clinical Impact: Studies have shown some antiretroviral protease inhibitors (PIs) with CYP3A4 inhibitory activity (nelfinavir, lopinavir/ritonavir, ritonavir) have little effect on buprenorphine pharmacokinetic and no significant pharmacodynamic effects. Other PIs with CYP3A4 inhibitory activity (atazanavir and atazanavir/ritonavir) resulted in elevated levels of buprenorphine and norbuprenorphine, and patients in one study reported increased sedation. Symptoms of opioid excess have been found in post-marketing reports of patients receiving buprenorphine and atazanavir with and without ritonavir concomitantly.
Intervention: Monitor patients taking buprenorphine sublingual tablets and atazanavir with and without ritonavir, and reduce dose of buprenorphine sublingual tablets if warranted.
Examples: atazanavir, ritonavir
Antiretrovirals: Nucleoside reverse transcriptase inhibitors (NRTIs)
Clinical Impact: Nucleoside reverse transcriptase inhibitors (NRTIs) do not appear to induce or inhibit the P450 enzyme pathway, thus no interactions with buprenorphine are expected.
Intervention: None
Serotonergic Drugs
Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue buprenorphine sublingual tablets if serotonin syndrome is suspected.
Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma).
Intervention: The use of buprenorphine sublingual tablets is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples: phenelzine, tranylcypromine, linezolid
Muscle Relaxants
Clinical Impact: Buprenorphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention: Monitor patients receiving muscle relaxants and buprenorphine sublingual tablets for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of buprenorphine sublingual tablets and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when buprenorphine sublingual tablets are used concomitantly with anticholinergic drugs.


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Figure 6: Mean Standing Systolic Blood Pressure Change from Baseline


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Table 4. Drugs That May Alter Hepatic Metabolism of T4 (Hypothyroidism)
Potential impact: Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased SYNTHROID requirements.
Drug or Drug Class Effect
Phenobarbital
Rifampin
Phenobarbital has been shown to reduce the response to thyroxine. Phenobarbital increases L-thyroxine metabolism by inducing uridine 5’-diphospho-glucuronosyltransferase (UGT) and leads to a lower T4 serum levels. Changes in thyroid status may occur if barbiturates are added or withdrawn from patients being treated for hypothyroidism. Rifampin has been shown to accelerate the metabolism of levothyroxine.


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Table 6: Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology (12.3)]
 Drug/Drug Class
(Mechanism of Interaction by the Drug)
 Voriconazole Plasma Exposure
(C max and AUC τ after
200 mg q12h)
  Recommendations for Voriconazole
Dosage Adjustment/Comments
 Rifampin* and Rifabutin*
(CYP450 Induction)
 Significantly Reduced  Contraindicated
 Efavirenz (400 mg q24h)**
(CYP450 Induction)
 Significantly Reduced  Contraindicated 
 Efavirenz (300 mg q24h)**
(CYP450 Induction)
Slight Decrease in AUCτ  When voriconazole is coadministered
with efavirenz, voriconazole oral
maintenance dose should be increased
to 400 mg q12h and efavirenz should
be decreased to 300 mg q24h 
 High-dose Ritonavir (400 mg q12h)**
(CYP450 Induction)
 Significantly Reduced  Contraindicated
 Low-dose Ritonavir (100 mg q12h)**
(CYP450 Induction)
 Reduced  Coadministration of voriconazole and
low-dose ritonavir (100 mg q12h)
should be avoided, unless an
assessment of the benefit/risk to the
patient justifies the use of voriconazole
 Carbamazepine
(CYP450 Induction)
 Not Studied In Vivo or In Vitro,
but Likely to Result in
Significant Reduction
 Contraindicated
 Long Acting Barbiturates
(CYP450 Induction)
 Not Studied In Vivo or In Vitro,
but Likely to Result in
Significant Reduction
 Contraindicated
 Phenytoin*
(CYP450 Induction)
 Significantly Reduced Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h
(100 mg to 200 mg orally q12h in patients weighing less than 40 kg)
 St. John’s Wort
(CYP450 inducer; P-gp inducer)
 Significantly Reduced  Contraindicated
 Oral Contraceptives**
containing ethinyl estradiol and
norethindrone (CYP2C19 Inhibition)
 Increased  Monitoring for adverse events and
toxicity related to voriconazole is
recommended when coadministered
with oral contraceptives
 Fluconazole** (CYP2C9, CYP2C19 and
CYP3A4 Inhibition)
 Significantly Increased  Avoid concomitant administration of
voriconazole and fluconazole.
Monitoring for adverse events and
toxicity related to voriconazole is
started within 24 h after the last dose of
fluconazole.
 Other HIV Protease Inhibitors
(CYP3A4 Inhibition)
 In Vivo Studies Showed No
Significant Effects of Indinavir
on Voriconazole Exposure
 No dosage adjustment in the
voriconazole dosage needed when
coadministered with indinavir
   In Vitro Studies Demonstrated
Potential for Inhibition of
Voriconazole Metabolism
(Increased Plasma Exposure)
 Frequent monitoring for adverse events
and toxicity related to voriconazole
when coadministered with other HIV
protease inhibitors
 Other NNRTIs***
(CYP3A4 Inhibition or CYP450 Induction)
 In Vitro Studies Demonstrated
Potential for Inhibition of
Voriconazole Metabolism by
Delavirdine and Other NNRTIs
(Increased Plasma Exposure)
 Frequent monitoring for adverse events
and toxicity related to voriconazole
   A Voriconazole-Efavirenz Drug
Interaction Study Demonstrated
the Potential for the Metabolism
of Voriconazole to be Induced by
Efavirenz and Other NNRTIs
(Decreased Plasma Exposure)
 Careful assessment of voriconazole
effectiveness


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Table 4. Other Potentially Significant Drug Interactions
Concomitant Drug Class or Food Noted or Anticipated Outcome Clinical Comment
HMG-Co A Reductase Inhibitors:
atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin
Pharmacokinetic and/or pharmacodynamic interaction: the addition of one drug to a stable long-term regimen of the other has resulted in myopathy and rhabdomyolysis (including a fatality) P-gp substrate; rhabdomyolysis has been reported Weigh the potential benefits and risks and carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during initial therapy; monitoring CPK (creatine phosphokinase) will not necessarily prevent the occurrence of severe myopathy.
Other Lipid-Lowering Drugs:
fibrates, gemfibrozil
Digitalis Glycosides:
digoxin


Table name:
AED Coadministered AED Concentration Topiramate Concentration
Phenytoin
NC or 25% increasePlasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
48% decrease


Carbamazepine (CBZ)
NC
40% decrease
CBZ epoxideIs not administered but is an active metabolite of carbamazepine.
NC
NE
Valproic acid
11% decrease
14% decrease
Phenobarbital
NC
NE
Primidone
NC
NE
Lamotrigine
NC at TPM doses up to 400 mg/day
13% decrease


Table name:
Concomitant Drug Name or Drug Class
Clinical Rationale
Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine)
The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].
With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)
The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].
With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Antihypertensive Drugs
Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.
Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.8)].
Benzodiazepines (e.g., lorazepam)
The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.8)]
Monitor sedation and blood pressure. Adjust dose accordingly.


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Drug Interactions Associated with Increased Risk of  Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice Avoid grapefruit juice


Table name:
Bleeding times
Clinical Impact: Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention: This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact: The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention: Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact: Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention: This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.


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Table 12: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction
Drugs Effect on Concentration Clinical Comment
Antiretroviral Agents: Nucleoside Reverse Transcriptase Inhibitors (NRTIs):
zidovudine
↔ zidovudine Monitor blood cell count and suppressive effect on bone marrow function when zidovudine is coadministered with PegIntron.
Immunosuppressants:
e.g.,
cyclosporine
sirolimus
tacrolimus
Effect on immunosuppressants unknown Therapeutic monitoring of the immunosuppressive agents is recommended upon coadministration with PegIntron.
Narcotic Analgesics:
methadone
↑ methadone Methadone dosage may need to be reduced when coadministered with PegIntron.
Neuroleptics:
thioridazine
↑ thioridazine Monitor for thioridazine adverse events when coadministered with PegIntron.
Xanthines:
theophylline
↑ theophylline Monitor for theophylline adverse events when coadministered with PegIntron.


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Table 4: Clinically Important Drug Interactions with VIIBRYD
Concomitant Drug Name or Drug Class Clinical Rationale Clinical Recommendation
Monoamine Oxidase Inhibitors (MAOIs) The concomitant use of MAOIs and serotonergic drugs including VIIBRYD increases the risk of serotonin syndrome. VIIBRYD is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [see Contraindications (4), Dosage and Administration (2.3), and Warnings and Precautions (5.2)].
Other Serotonergic Drugs The concomitant use of serotonergic drugs including VIIBRYD and other serotonergic drugs increases the risk of serotonin syndrome. Monitor patients for signs and symptoms of serotonin syndrome, particularly during VIIBRYD initiation. If serotonin syndrome occurs, consider discontinuation of VIIBRYD and/or concomitant serotonergic drugs [see Warnings and Precautions (5.2)].
Antiplatelet Agents and Anticoagulants Serotonin release by platelets plays an important role in hemostasis. The concurrent use of an antiplatelet agent or anticoagulant with VIIBRYD may potentiate the risk of bleeding. Inform patients of the increased risk of bleeding with the concomitant use of VIIBRYD and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio (INR) when initiating or discontinuing VIIBRYD [see Warnings and Precautions (5.3)].
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin, voriconazole) The concomitant use of VIIBRYD and strong CYP3A4 inhibitors increased the exposure of vilazodone compared to the use of VIIBRYD alone [see Clinical Pharmacology (12.3)]. The VIIBRYD dose should not exceed 20 mg once daily with the concomitant use of a strong CYP3A4 inhibitor [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].
Strong CYP3A4 Inducers (e.g.,
carbamazepine, phenytoin, rifampin)
The concomitant use of VIIBRYD and strong CYP3A4 inducers decreased the exposure of vilazodone compared to the use of VIIBRYD alone [see Clinical Pharmacology (12.3)]. Based on clinical response, consider increasing the dosage of VIIBRYD, over 1 to 2 weeks in patients taking strong CYP3A4 inducers for greater than 14 days [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].
Digoxin Digoxin is a narrow therapeutic index drug. Concomitant use of VIIBRYD increased digoxin concentrations [see Clinical Pharmacology (12.3)]. Measure serum digoxin concentrations before initiating concomitant use of VIIBRYD. Continue monitoring and reduce digoxin dose as necessary.


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Table II. Clinically significant drug interactions with theophylline Refer to PRECAUTIONS, Drug Interactions for further information regarding table. .
Drug Type of Interaction Effect Average effect on steady state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.
Adenosine Theophylline blocks adenosine receptors. Higher doses of adenosine may be required to achieve desired effect.
Alcohol A single large dose of alcohol (3 ml/kg of whiskey) decreases theophylline clearance for up to 24 hours. 30% increase
Allopurinol Decreases theophylline clearance doses ≥600 mg/day. 25% increase at allopurinol
Amino glutethimide Increases theophylline clearance by induction of microsomal enzyme activity. 25% decrease
Carbamazepine Similar to aminoglutethimide. 30% decrease
Cimetidine Decreases theophylline clearance by inhibiting cytochrome P450 1A2. 70% increase
Ciprofloxacin Similar to cimetidine. 40% increase
Clarithromycin Similar to erythromycin. 25% decrease
Diazepam Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. Large diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram Decreases theophylline clearance by inhibiting hydroxylation and demethylation. 50% increase
Enoxacin Similar to cimetidine. 300% increase
Ephedrine Synergistic CNS effects. Increased frequency of nausea, nervousness, and insomnia.
Erythromycin Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3. 35% increase.
Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown. 30% increase
Flurazepam Similar to diazepam. Similar to diazepam.
Fluvoxamine Similar to cimetidine. Similar to cimetidine.
Halothane Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines. Increased risk of ventricular arrhythmias
Interferon, human recombinant alpha-A Decreases theophylline clearance. 100% increase
Isoproterenol (IV) Increases theophylline 20% decrease
Ketamine Pharmacologic May lower theophylline seizure threshold.
Lithium Theophylline increases renal lithium clearance. Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam Similar to diazepam. Similar to diazepam.
Methotrexate (MTX) Decreases theophylline clearance. 20% increase after low dose MTX, higher dose MTX may have a greater effect.
Mexiletine Similar to disulfiram. 80% increase
Midazolam Similar to diazepam. Similar to diazepam.
Moricizine Increases theophylline clearance. 25% decrease
Pancuronium Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition. Larger dose of pancuronium may be required to achieve neuromuscular blockade.
Pentoxifyline (PB) Similar to aminogluethimide. 25% decrease after two weeks of concurrent PB.
Phenytoin Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption. Serum theophylline and phenytoin concentrations decrease about 40%.
Propafenone Decreases theophylline clearance and pharmacologic interaction. 40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Propranolol Similar to cimetidine and pharmacologic interaction. 100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Rifampin Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity. 20-40% decrease
Sulfinpyrazone Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline. 20% decrease
Tacrine Similar to cimetidine, also increases renal clearance to theophylline. 90% increase
Thiabendazole Decreases theophylline clearance. 190% increase
Ticlopidine Decreases theophylline clearance. 60% increase
Troleandomycin Similar to erythromycin. 33-100% increase depending on troleandomycin dose.
Verapamil Similar to disulfiram. 20% increase


Table name:
Drugs That Increase Cyclosporine Concentrations
Calcium Channel Blockers Antifungals Antibiotics Glucocorticoids Other Drugs
diltiazem nicardipine verapamil   fluconazole itraconazole ketoconazole voriconazole   azithromycin clarithromycin erythromycin quinupristin/ dalfopristin   methylprednisolone   allopurinol amiodarone bromocriptine colchicine danazol imatinib metoclopramide nefazodoneoral contraceptives


Table name:
Drugs That Interfere with Hemostasis
Clinical Impact:
• Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone.
• Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.


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Table 2:   Examples of CYP450 Interactions with Warfarin
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Drug/Drug Class
(Mechanism of Interaction by Voriconazole)
Drug Plasma Exposure
(C max and AUC τ)
Recommendations for Drug Dosage Adjustment/Comments
Sirolimus Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects
(CYP3A4 Inhibition)
Significantly Increased Contraindicated
Rifabutin
(CYP3A4 Inhibition)
Significantly Increased Contraindicated
Efavirenz (400 mg q 24h) Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects
(CYP3A4 Inhibition)
Efavirenz (300 mg q 24h) (CYP3A4 Inhibition)
Significantly Increased Slight decrease in AUC t Contraindicated When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)
(CYP3A4 Inhibition)
No Significant Effect of Voriconazole on Ritonavir C max or AUC τ Contraindicated because of significant reduction of voriconazole C max and AUCτ
Low-dose Ritonavir (100 mg q12h) Slight Decrease in Ritonavir C max and AUC τ Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole C max and AUC τ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine
(CYP3A4 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids
(CYP450 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Contraindicated
Cyclosporine
(CYP3A4 Inhibition)
AUC τ Significantly Increased; No Significant Effect on C max When initiating therapy with voriconazole in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When voriconazole is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
Methadone Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for 4 days voriconazole to subjects receiving a methadone maintenance dose (30 to 100 mg q24h)
(CYP3A4 Inhibition)
Increased Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl
(CYP3A4 Inhibition)
Increased Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary [ see Drug Interactions ( 7) ]
Alfentanil
(CYP3A4 Inhibition)
Significantly Increased Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with voriconazole. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [ see Drug Interactions ( 7) ].
Oxycodone
(CYP3A4 Inhibition)
Significantly Increased Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary [ see Drug Interactions ( 7) ].
NSAIDs Non-Steroidal Anti-Inflammatory Drug including ibuprofen and diclofenac (CYP2C9 Inhibition) Increased Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed. [ see Drug Interactions ( 7) ].
Tacrolimus (CYP3A4 Inhibition) Significantly Increased When initiating therapy with voriconazole in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazole is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin (CYP2C9 Inhibition) Significantly Increased Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition) Increased Monitoring for adverse events related to oral contraceptives is recommended during coadministration.
Warfarin (CYP2C9 Inhibition) Prothrombin Time Significantly Increased Monitor PT or other suitable anticoagulation tests. Adjustment of warfarin dosage may be needed.
Omeprazole (CYP2C19/3A4 Inhibition) Significantly Increased When initiating therapy with voriconazole in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors (CYP3A4 Inhibition) In Vivo Studies Showed No Significant Effects on Indinavir Exposure No dosage adjustment for indinavir when coadministered with voriconazole
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors
Other NNRTIs Non-Nucleoside Reverse Transcriptase Inhibitors (CYP3A4 Inhibition) A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to NNRTI
Benzodiazepines (CYP3A4 Inhibition) In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.
HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition) In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition) In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition) Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed.
Everolimus (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Concomitant administration of voriconazole and everolimus is not recommended


Table name:
Drug Type of Interaction Effect**

Adenosine

Theophylline blocks adenosine receptors.

Higher doses of adenosine may be required to achieve desired effect.

Alcohol 

A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours.

30% increase 

Allopurinol 

Decreases theophylline clearance at allopurinol doses ≥600 mg/day.

25% increase 

Aminoglutethimide

Increases theophylline clearance by induction of microsomal enzyme activity.

25% decrease 

Carbamazepine

Similar to aminoglutethimide.

30% decrease

Cimetidine

Decreases theophylline clearance by inhibiting cytochrome P450 1A2.

70% increase

Ciprofloxacin

Similar to cimetidine.

40% increase

Clarithromycin

Similar to erythromycin.

25% increase

Diazepam  

Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. 

Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.

Disulfiram 

Decreases theophylline clearance by inhibiting hydroxylation and demethylation.

50% increase 

Enoxacin

Similar to cimetidine.

300% increase

Ephedrine

Synergistic CNS effects.

Increased frequency of nausea, nervousness, and insomnia.

Erythromycin 

 

Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3.

35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.

Estrogen 

Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown.

30% increase 

 

 

Flurazepam

Similar to diazepam.

Similar to diazepam.

Fluvoxamine

Similar to cimetidine.

Similar to cimetidine.

Halothane  

Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines.

Increased risk of ventricular arrhythmias. 

Interferon, human recombinant alpha-A

Decreases theophylline clearance.

100% increase 

Isoproterenol (IV)

Increases theophylline clearance.

20% decrease

Ketamine 

Pharmacologic. 

May lower theophylline seizure threshold

Lithium

Theophylline increases renal lithium clearance.

Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.

Lorazepam

Similar to diazepam.

Similar to diazepam.

Methotrexate (MTX)

Decreases theophylline clearance.

 

20% increase after low dose MTX, higher dose MTX may have a greater effect.

Mexiletine

Similar to disulfiram.

80% increase

Midazolam

Similar to diazepam.

Similar to diazepam.

Moricizine

Increases theophylline clearance.

25% decrease

Pancuronium 

Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition.

Larger dose of pancuronium may be required to achieve neuromuscular blockade.

Pentoxifylline

Decreases theophylline clearance.

 30% increase

Phenobarbital (PB) 

Similar to aminoglutethimide. 

25% decrease after two weeks of concurrent PB.

Phenytoin

Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption.

Serum theophylline and phenytoin concentrations decrease about 40%.

Propafenone 

Decreases theophylline clearance and pharmacologic interaction. 

40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.

Propranolol 

Similar to cimetidine and pharmacologic interaction. 

100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.

Rifampin 

Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity.

20-40% decrease 
St. John’sWort (Hypericum Perforatum) Decrease in theophylline plasma concentrations. Higher doses of theophylline may be required to achieve desired effect. Stopping St. John’s Wort may result in theophylline toxicity.

Sulfinpyrazone

Increase theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline.

20% decrease

Tacrine

Similar to cimetidine, also increases renal clearance of theophylline.

90% increase

Thiabendazole

Decreases theophylline clearance.

190% increase

Ticlopidine

Decreases theophylline clearance.

60% increase

Troleandomycin 

Similar to erythromycin. 

33-100% increase depending on troleandomycin dose.

Verapamil

Similar to disulfiram.

20% increase


Table name:
Table III. Drugs That Have Been Documented Not to Interact With Theophylline or Drugs That Produce No Clinically Significant Interaction With Theophylline*
albuterol, systemic and inhaled amoxicillin ampicillin, with or without sulbactam atenolol azithromycin caffeine, dietary ingestion cefaclor co-trimoxazole (trimethoprim and sulfamethoxazole) diltiazem dirithromycin enflurane famotidine felodipine finasteride hydrocortisone isoflurane isoniazid isradipine influenza vaccine ketoconazole lomefloxacin mebendazole medroxyprogesterone methylprednisolone metronidazole metoprolol nadolol nifedipine nizatidine norfloxacin ofloxacin omeprazole prednisone, prednisolone ranitidine rifabutin roxithromycin sorbitol (purgative doses do not inhibit theophylline absorption) sucralfate terbutaline, systemic terfenadine tetracycline tocainide
* Refer to PRECAUTIONS , Drug Interactions for information regarding table.


Table name:
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)   Avoid atorvastatin  
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) Do not exceed 40 mg atorvastatin daily


Table name:
 Concomitant Drug   Effect on
Concentration of
Lamotrigine or
Concomitant Drug
 Clinical Comment
Estrogen-containing oral contraceptivepreparation containing
30 mcg ethinylestradiol
and 150 mcg
levonorgestrel
 ↓ lamotrigine
 
 
 
↓ levonorgestrel
 Decreased lamotrigine levels approximately 50%.
 
 
Decrease in levonorgestrel component by 19%.
 Carbamazepine
and carbamazepine epoxide
 ↓ lamotrigine
 
 
 
? carbamazepine epoxide
 Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
 
May increase carbamazepine epoxide levels.
 Lopinavir/ritonavir  ↓ lamotrigine  Decreased lamotrigine concentration approximately 50%.
 Atazanavir/ritonavir  ↓ lamotrigine  Decreased lamotrigine AUC approximately 32%.
 Phenobarbital/primidone    ↓ lamotrigine  Decreased lamotrigine concentration approximately 40%.
 Phenytoin   ↓ lamotrigine  Decreased lamotrigine concentration approximately 40%.
 Rifampin   ↓ lamotrigine  Decreased lamotrigine AUC approximately 40%.
 Valproate   ↑ lamotrigine
 
 
 
? valproate
  Increased lamotrigine concentrations slightly more than 2-fold.
 
There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.


Table name:
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin dailyFor patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice Avoid grapefruit juice


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T 4 and T 3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT 4. Continued administration results in a decrease in serum T 4 and normal FT 4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T 4 and T 3 to TBG and transthyretin. An initial increase in serum FT 4, is followed by return of FT 4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T 4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T 4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T 4 to T 3, leading to decreased T 3 levels. However, serum T 4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T 3 and T 4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T 3 concentrations by 30% with minimal change in serum T 4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T 3 and T 4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 3: Clinically Important Drug Interactions with Repaglinide
 Gemfibrozil
Clinical Impact:
Gemfibrozil significantly increased repaglinide exposures by 8.1 fold [see Clinical Pharmacology (12.3)]
Intervention:
Do not administer repaglinide to patients receiving gemfibrozil [see Contraindications (4)].
 Clopidogrel
Clinical Impact:
Clopidogrel increased repaglinide exposures by 3.9 to 5.1 fold [see Clinical Pharmacology (12.3)]
Intervention:
Avoid concomitant use of repaglinide with clopidogrel. If concomitant use can not be avoided, initiate repaglinide at 0.5 mg before each meal and do not exceed a total daily dose of 4 mg [see DOSAGE AND ADMINISTRATION (2.3)]. Increased frequency of glucose monitoring may be required during concomitant use.
 Cyclosporine
Clinical Impact:
Cyclosporine increased low dose repaglinide exposures by 2.5 fold [see Clinical Pharmacology (12.3)]
Intervention:
Daily maximum repaglinide dose should be limited to 6 mg, and increased frequency of glucose monitoring may be required when repaglinide is co-administered with cyclosporine.
 CYP2C8 and CYP3A4 Inhibitors
Intervention:
Repaglinide dose reductions and increased frequency of glucose monitoring may be required when co­-administered.
Examples:
Drugs that are known to inhibit CYP3A4 include antifungal agents (ketoconazole, itraconazole) and antibacterial agents (clarithromycin, erythromycin). Drugs that are known to inhibit CYP2C8 include trimethoprim, gemfibrozil, montelukast, deferasirox, and clopidiogrel.
 CYP2C8 and CYP3A4 Inducers
Intervention:
Repaglinide dose increases and increased frequency of glucose monitoring may be required when co-­administered.
Examples:
Drugs that induce the CYP3A4 and/or 2C8 enzyme systems include rifampin, barbiturates, and carbamezapine
 Drugs That May Increase the Risk of Hypoglycemia
Intervention:
Repaglinide dose reductions and increased frequency of glucose monitoring may be required when co-­administered.
Examples:
Antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, nonsteroidal anti-inflammatory agents (NSAIDs), pentoxifylline, pramlintide, propoxyphene, salicylates, somatostatin analogs (e.g., octreotide), and sulfonamide antibiotics
 Drugs That May Decrease the Blood Glucose Lowering Effect of Repaglinide
Intervention:
Repaglinide dose increases and increased frequency of glucose monitoring may be required when co-­administered.
Examples:
Atypical antipsychotics (e.g., olanzapine and clozapine), calcium channel antagonists, corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones.
 Drugs That May Blunt Signs and Symptoms of Hypoglycemia
Intervention:
Increased frequency of glucose monitoring may be required when repaglinide is co-administered with these drugs.
Examples:
beta-blockers, clonidine, guanethidine, and reserpine


Table name:
Interacting Drug
Interaction
Theophylline
Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin
Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents
Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin
Monitor phenytoin level (7)
Methotrexate
Monitor for methotrexate toxicity (7)
Cyclosporine
May increase serum creatinine. Monitor serum creatinine (7)
Multivalent cation-containing products including antacids, metal cations or didanosine
Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin (7)


Table name:
Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s) Recommendation Comments
Tizanidine Contraindicated Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)].
Theophylline Avoid Use (Plasma Exposure Likely to be Increased and Prolonged) Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions (5.6).]
Drugs Known to Prolong QT Interval Avoid Use Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.10) and Use in Specific Populations (8.5)].
Oral antidiabetic drugs Use with caution Glucose-lowering effect potentiated Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported . Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs. [see Adverse Reactions (6.1).]
Phenytoin Use with caution Altered serum levels of phenytoin (increased and decreased) To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after coadministration of ciprofloxacin with phenytoin.
Cyclosporine Use with caution (transient elevations in serum creatinine) Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs Use with caution (Increase in anticoagulant effect) The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole Use with caution Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after coadministration with ciprofloxacin [see Warnings and Precautions (5.15)].
Clozapine Use with caution Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs Use with caution Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil Use with caution 2-fold increase in exposure Monitor for sildenafil toxicity (see Pharmacokinetics -(12.3)-] .
Duloxetine Avoid Use 5-fold increase in duloxetine exposure If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx ® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products) Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2)]. Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels) Potentiation of ciprofloxacin toxicity may occur.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
 Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)  Avoid atorvastatin
 HIV protease inhibitor (lopinavir plus ritonavir)  Use with caution and lowest dose necessary
 Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir )  Do not exceed 20 mg atorvastatin daily
 HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
 Do not exceed 40 mg atorvastatin daily


Table name:
Dosage adjustment due to drug interactions (7.1):
  Factors   Dosage Adjustments for Aripiprazole
  Known CYP2D6 Poor Metabolizers   Administer half of usual dose
  Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors   Administer a quarter of usual dose
  Strong CYP2D6 or CYP3A4 inhibitors   Administer half of usual dose
  Strong CYP2D6 and CYP3A4 inhibitors   Administer a quarter of usual dose
  Strong CYP3A4 inducers   Double usual dose over 1 to 2 weeks


Table name:
Table 2. Drug Interactions: Pharmacokinetic Parameters for Azithromycin in the Presence of Coadministered Drugs (see PRECAUTIONS, Drug Interactions).
NA – Not available * - 90% Confidence interval not reported Mean azithromycin concentrations one day after the last dose were 53 ng/mL when coadministered with 300 mg daily rifabutin and 49 ng/mL when coadministered with placebo.
Coadministered Drug   Dose of Coadministered Drug Dose of Azithromycin n Ratio (with/without coadministered drug) of Azithromycin Pharmacokinetic Parameters (90% CI); No Effect = 1.00
Mean Cmax Mean AUC
Efavirenz 400 mg/day x 7 days 600 mg PO on day 7 14 1.22 (1.04 to 1.42) 0.92*
Fluconazole 200 mg PO single dose 1,200 mg PO single dose 18 0.82 (0.66 to 1.02) 1.07 (0.94 to 1.22)
Nelfinavir 750 mg TID x 11 days 1,200 mg PO on day 9 14 2.36 (1.77 to 3.15) 2.12 (1.80 to 2.50)
Rifabutin 300 mg/day x 10 days 500 mg PO on day 1, then 250 mg/day on days 2 to 10 6 See footnote below NA


Table name:
Table 5. Clinically-Significant Drug Interactions with Sertraline Hydrochloride
Monoamine  Oxidase  Inhibitors  ( MAOIs )
Clinical  Impact :
The concomitant use of SSRIs including sertraline hydrochloride and MAOIs increases the risk of serotonin syndrome.
Intervention :
Sertraline hydrochloride is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue  [ See  Dosage  and  Administration  ( 2 . 5 ),  Contraindications  ( 4 ),  Warnings  and  Precautions  ( 5 . 2)].
Examples :
selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue
Pimozide
Clinical  Impact :
Increased plasma concentrations of pimozide, a drug with a narrow therapeutic index, may increase the risk of QT prolongation and ventricular arrhythmias.
Intervention :
Concomitant use of pimozide and sertraline hydrochloride is contraindicated  [ See  Contraindications  ( 4)].
Other  Serotonergic  Drugs
Clinical  Impact :
The concomitant use of serotonergic drugs with sertraline hydrochloride increases the risk of serotonin syndrome.
Intervention :
Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of sertraline hydrochloride and/or concomitant serotonergic drugs  [ See  Warnings  and  Precautions  ( 5 . 2)].
Examples :
other SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort
Drugs  that  Interfere  with  Hemostasis  ( antiplatelet  agents  and  anticoagulants )
Clinical  Impact :
The concurrent use of an antiplatelet agent or anticoagulant with sertraline hydrochloride may potentiate the risk of bleeding.
Intervention :
Inform patients of the increased risk of bleeding associated with the concomitant use of sertraline hydrochloride and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio  [ See  Warnings  and  Precautions  ( 5 . 3)].
Examples :
aspirin, clopidogrel, heparin, warfarin
Drugs  Highly  Bound  to  Plasma  Protein
Clinical  Impact :
Sertraline hydrochloride is highly bound to plasma protein. The concomitant use of sertraline hydrochloride with another drug that is highly bound to plasma protein may increase free concentrations of sertraline hydrochloride or other tightly-bound drugs in plasma  [ See  Clinical  Pharmacology  ( 12 . 3 )].
Intervention :
Monitor for adverse reactions and reduce dosage of sertraline hydrochloride or other protein-bound drugs as warranted.
Examples :
warfarin
Drugs  Metabolized  by  CYP2D6
Clinical  Impact :
Sertraline hydrochloride is a CYP2D6 inhibitor  [ See  Clinical  Pharmacology  ( 12 . 3)]. The concomitant use of sertraline hydrochloride with a CYP2D6 substrate may increase the exposure of the CYP2D6 substrate.
Intervention :
Decrease the dosage of a CYP2D6 substrate if needed with concomitant sertraline hydrochloride use. Conversely, an increase in dosage of a CYP2D6 substrate may be needed if sertraline hydrochloride is discontinued.
Examples :
propafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, thoridazine, tolterodine, venlafaxine
Phenytoin
Clinical  Impact :
Phenytoin is a narrow therapeutic index drug. Sertraline hydrochloride may increase phenytoin concentrations.
Intervention :
Monitor phenytoin levels when initiating or titrating sertraline hydrochloride. Reduce phenytoin dosage if needed.
Examples :
phenytoin, fosphenytoin


Table name:
Interacting  Drug
Interaction
Multivalent cation-containing 
products including antacids, metal 
cations or didanosine
Do not co-administer the intravenous formulation  in the same IV line with a multivalent cation, e.g.,  magnesium (2.4, 7.1)
Warfarin
Effect may be enhanced. Monitor prothrombin  time, INR, watch for bleeding (7.2)
Antidiabetic agents
Carefully monitor blood glucose (5.12, 7.3)


Table name:
Table 2: Drug — Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion -the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine / Dopamine
Agonists Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥100 mg/day or equivalent); Octreotide (>100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T4 and T3 serum transport — but FT4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone > 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.


Table name:
Table 6: Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology (12.3)]
** Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg q12h voriconazole to healthy subjects
** Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects
*** Non-Nucleoside Reverse Transcriptase Inhibitors
Drug/Drug Class
(Mechanism of Interaction by the Drug)
Voriconazole Plasma Exposure
(Cmax and AUC τ after 200 mg q12h)
Recommendations for Voriconazole Dosage Adjustment/Comments
Rifampin* and Rifabutin*
(CYP450 Induction)
Significantly Reduced
Contraindicated
Efavirenz (400 mg q24h)**
(CYP450 Induction)
 
Efavirenz (300 mg q24h)**
(CYP450 Induction)
 
Significantly Reduced
 
 
Slight Decrease in  AUC τ
Contraindicated
 
 
When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)** (CYP450 Induction)
 
Low-dose Ritonavir (100 mg q12h)** (CYP450 Induction)
Significantly Reduced
 
 
Reduced
Contraindicated
 

Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Carbamazepine
(CYP450 Induction)
Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction
Contraindicated
Long Acting Barbiturates
(CYP450 Induction)
Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction
Contraindicated
Phenytoin*
(CYP450 Induction)
Significantly Reduced
Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg)
St. John’s Wort
(CYP450 inducer; P-gp inducer)
Significantly Reduced
Contraindicated
Oral Contraceptives** containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)
Increased
Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole** (CYP2C9, CYP2C19 and CYP3A4 Inhibition)
Significantly Increased
Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)
In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure
 
In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)
No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir
 
Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
 
Other NNRTIs***
(CYP3A4 Inhibition or CYP450 Induction)
In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure)
 
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure)
 
Frequent monitoring for adverse events and toxicity related to voriconazole
 
 
 
 
Careful assessment of voriconazole  effectiveness
 


Table name:
Inhibitors of CYP2D6
Clinical Impact:
The concomitant use of tramadol hydrochloride extended-release tablets and CYP2D6 inhibitors may result in an increase in the plasma concentration of tramadol and a decrease in the plasma concentration of M1, particularly when an inhibitor is added after a stable dose of tramadol hydrochloride extended-release tablets is achieved. Since M1 is a more potent μ-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome.
 
After stopping a CYP2D6 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease and the M1 plasma concentration will increase which could increase or prolong therapeutic effects but also increase adverse reactions related to opioid toxicity, and may cause potentially fatal respiratory depression [see Clinical Pharmacology (12.3)].
Intervention:
If concomitant use of a CYP2D6 inhibitor is necessary, follow patients closely for adverse reactions including opioid withdrawal, seizures, and serotonin syndrome.
 
If a CYP2D6 inhibitor is discontinued, consider lowering tramadol hydrochloride extended-release tablets dosage until stable drug effects are achieved. Follow patients closely for adverse events including respiratory depression and sedation.
Examples
Quinidine, fluoxetine, paroxetine and bupropion
Inhibitors of CYP3A4
Clinical Impact:
The concomitant use of tramadol hydrochloride extended-release tablets and CYP3A4 inhibitors can increase the plasma concentration of tramadol and may result in a greater amount of metabolism via CYP2D6 and greater levels of M1. Follow patients closely for increased risk of serious adverse events including seizures and serotonin syndrome, and adverse reactions related to opioid toxicity including potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of tramadol hydrochloride extended-release tablets is achieved.
 
After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy and possibly signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol.
Intervention:
If concomitant use is necessary, consider dosage reduction of tramadol hydrochloride extended-release tablets until stable drug effects are achieved. Follow patients closely for seizures and serotonin syndrome, and signs of respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the tramadol hydrochloride extended-release tablets dosage until stable drug effects are achieved and follow patients for signs and symptoms of opioid withdrawal.
Examples
Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir)
CYP3A4 Inducers
Clinical Impact:
The concomitant use of tramadol hydrochloride extended-release tablets and CYP3A4 inducers can decrease the plasma concentration of tramadol [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to tramadol, [see Warnings and Precautions (5.5)].
 
After stopping a CYP3A4 inducer, as the effects of the inducer decline, the tramadol plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause seizures and serotonin syndrome, and potentially fatal respiratory depression.
Intervention:
If concomitant use is necessary, consider increasing the tramadol hydrochloride extended-release tablets dosage until stable drug effects are achieved. Follow patients for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider tramadol hydrochloride extended-release tablets dosage reduction and monitor for seizures and serotonin syndrome, and signs of sedation and respiratory depression.
 
Patients taking carbamazepine, a CYP3A4 inducer, may have a significantly reduced analgesic effect of tramadol. Because carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of tramadol hydrochloride extended-release tablets and carbamazepine is not recommended.
Examples:
Rifampin, carbamazepine, phenytoin
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact:
Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:
Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.6)].
Examples:
Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact:
The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention:
If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue tramadol hydrochloride extended-release tablets if serotonin syndrome is suspected.
Examples:
Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:
MAOI interactions with opioids may manifest as serotonin syndrome [see Warnings and Precautions (5.7)] or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)].
Intervention:
Do not use tramadol hydrochloride extended-release tablets in patients taking MAOIs or within 14 days of stopping such treatment.
Examples:
phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:
May reduce the analgesic effect of tramadol hydrochloride extended-release tablets and/or precipitate withdrawal symptoms.
Intervention:
Avoid concomitant use.
Examples:
butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact:
Tramadol may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:
Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of tramadol hydrochloride extended-release tablets and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact:
Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:
Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:
The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:
Monitor patients for signs of urinary retention or reduced gastric motility when tramadol hydrochloride extended-release tablets is used concomitantly with anticholinergic drugs.
Digoxin
Clinical Impact:
Post-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity.
Intervention:
Follow patients for signs of digoxin toxicity and adjust the dosage of digoxin as needed.
Warfarin
Clinical Impact:
Post-marketing surveillance of tramadol has revealed rare reports of alteration of warfarin effect, including elevation of prothrombin times.
Intervention:
Monitor the prothrombin time of patients on warfarin for signs of an interaction and adjust the dosage of warfarin as needed.


Table name:
Table 4 Other Potentially Significant Drug Interactions
Concomitant Drug Class or Food Noted or Anticipated Outcome Clinical Comment
HMG-Co A Reductase Inhibitors:
atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin
Pharmacokinetic and/or pharmacodynamic interaction: the addition of one drug to a stable long-term regimen of the other has resulted in myopathy and rhabdomyolysis (including a fatality) Weigh the potential benefits and risks and carefully monitor patients for any signs or symptoms of muscle pain, tenderness or weakness, particularly during initial therapy; monitoring CPK (creatine phosphokinase) will not necessarily prevent the occurrence of severe myopathy.
Other Lipid Lowering Drugs:
fibrates, gemfibrozil
Digitalis Glycosides:
digoxin
P-gp substrate; rhabdomyolysis has been reported


Table name:
Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme
Inhibitors
Inducers
CYP2C9 
amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast
aprepitant, bosentan, carbamazepine, phenobarbital, rifampin 
CYP1A2 
acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton
montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking 
CYP3A4 
alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton
armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide 


Table name:
AED Coadministered AED Concentration Topiramate Concentration
Phenytoin NC or 25% increasea 48% decrease
Carbamazepine (CBZ) NC 40% decrease
CBZ epoxideb NC NE
Valproic acid 11% decrease 14% decrease
Phenobarbital NC NE
Primidone NC NE
Lamotrigine NC at TPM doses up to 400 mg/day 13% decrease


Table name:
Table 2:   Examples of CYP450 Interactions with Warfarin
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Drugs That Interfere with Hemostasis
Clinical Impact:
Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:
Monitor patients with concomitant use of naproxen with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact:
Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].
Intervention:
Concomitant use of naproxen and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)].
Naproxen are not substitutes for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:
NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:
During concomitant use of naproxen and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of naproxen and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:
Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:
During concomitant use of naproxen with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Digoxin
Clinical Impact:
The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin
Intervention:
During concomitant use of naproxen and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:
NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:
During concomitant use of naproxen and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:
Concomitant use of  NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:
During concomitant use of naproxen and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:
Concomitant use of naproxen and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:
During concomitant use of naproxen and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:
Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention:
The   concomitant   use   of   naproxen   with   other   NSAIDs   or   salicylates   is   not recommended.
Pemetrexed
Clinical Impact:
Concomitant use of naproxen and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:
During concomitant use of naproxen and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.
NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.
In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact:
Concomitant  administration  of  some  antacids  (magnesium  oxide  or  aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention:
Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen is not recommended.
Cholestyramine
Clinical Impact:
Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention:
Concomitant  administration   of  cholestyramine   with  naproxen is not recommended.
Probenecid
Clinical Impact:
Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention:
Patients   simultaneously   receiving   naproxen and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact:
Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention:
Patients simultaneously receiving naproxen and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.


Table name:
Drugs That Are Affected By Clarithromycin
Drug(s) with Pharmacokinetics Affected by Clarithromycin Recommendation Comments
Antiarrhythmics:
Disopyramide
Quinidine
Dofetilide
Amiodarone
Sotalol
Procainamide               
Not Recommended                 Disopyramide, Quinidine: There have been postmarketing reports of torsades de pointes occurring with concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QTc prolongation during coadministration of clarithromycin with these drugs [see Warnings and Precautions (5.3)].
Serum concentrations of these medications should also be monitored. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with disopyramide and quinidine.
There have been postmarketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide. Therefore, blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide.
Digoxin Use With Caution Digoxin: Digoxin is a substrate for P-glycoprotein (Pgp) and clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are co­ administered, inhibition of Pgp by clarithromycin may lead to increased exposure of digoxin. Elevated digoxin serum concentrations in patients receiving clarithromycin and digoxin concomitantly have been reported in postmarketing surveillance. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Monitoring of serum digoxin concentrations should be considered, especially for patients with digoxin concentrations in the upper therapeutic range.
Oral Anticoagulants:
Warfarin
 Use With Caution Oral anticoagulants: Spontaneous reports in the postmarketing period suggest that concomitant administration of clarithromycin and oral anticoagulants may potentiate the effects of the oral anticoagulants. Prothrombin times should be carefully monitored while patients are receiving clarithromycin and oral anticoagulants simultaneously [see Warnings and Precautions (5.4)].
Antiepileptics:
Carbamazepine
 Use With Caution Carbamazepine: Concomitant administration of single doses of clarithromycin and carbamazepine has been shown to result in increased plasma concentrations of carbamazepine. Blood level monitoring of carbamazepine may be considered. Increased serum concentrations of carbamazepine were observed in clinical trials with clarithromycin. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with carbamazepine.
Antifungals:
Itraconazole            
  Use With Caution Itraconazole: Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when administered concomitantly (see also Itraconazole under "Drugs That Affect clarithromycin" in the table below). Clarithromycin may increase the plasma concentrations of itraconazole. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions.
Fluconazole No Dose Adjustment Fluconazole: [see Pharmacokinetics (12.3)]
Anti-Gout Agents:
Colchicine (in patients with renal or hepatic impairment)
Colchicine (in patients with normal renal or hepatic function)
Contraindicated 
Use With Caution
Colchicine: Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. The dose of colchicine should be reduced when co-administered with clarithromycin in patients with normal renal and hepatic function [see Contraindications (4.4) and Warnings and Precautions (5.4)].
Antipsychotics:
Pimozide
Quetiapine
 Contraindicated  Pimozide: [See Contraindications (4.2)]
Qutiapine: Quetiapine is a substrate for CYP3A4, which is inhibited by clarithromycin. Co-­administration with clarithromycin could result in increased quetiapine exposure and possible quetiapine related toxicities. There have been postmarketing reports of somnolence, orthostatic hypotension, altered state of consciousness, neuroleptic malignant syndrome, and QT prolongation during concomitant administration. Refer to quetiapine prescribing information for recommendations on dose reduction if co-­ administered with CYP3A4 inhibitors such as clarithromycin. [See Contraindications (4.2)]
Antispasmodics:
Tolterodine (patients deficient in CYP2D6 activity)
 Use With Caution Tolterodine: The primary route of metabolism for tolterodine is via CYP2D6. However, in a subset of the population devoid of CYP2D6, the identified pathway of metabolism is via CYP3A. In this population subset, inhibition of CYP3A results in significantly higher serum concentrations of tolterodine. Tolterodine 1 mg twice daily is recommended in patients deficient in CYP2D6 activity (poor metabolizers) when co-administered with clarithromycin.
Antivirals:
Atazanavir
  Use With Caution Atazanavir: Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction (see Atazanavir under "Drugs That Affect clarithromycin" in the table below) [see Pharmacokinetics (12.3)].
Saquinavir (in patients with decreased renal function)   Saquinavir: Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A and there is evidence of a bi-directional drug interaction (see Saquinavir under "Drugs That Affect clarithromycin" in the table below) [see Pharmacokinetics (12.3)].
Ritonavir Etravirine   Ritonavir, Etravirine: (see Ritonavir and Etravirine under "Drugs That Affect clarithromycin" in the table below) [see Pharmacokinetics (12.3)].
Maraviroc   Maraviroc: Clarithromycin may result in increases in maraviroc exposures by inhibition of CYP3A metabolism. See Selzentry® prescribing information for dose recommendation when given with strong CYP3A inhibitors such as clarithromycin.
Boceprevir (in patients with normal renal function) 
Didanosine
No Dose Adjustment Boceprevir: Both clarithromycin and boceprevir are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when co­- administered. No dose adjustments are necessary for patients with normal renal function (see Victrelis® prescribing information).
Zidovudine   Zidovudine: Simultaneous oral administration of clarithromycin immediate-release tablets and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine concentrations. Administration of clarithromycin and zidovudine should be separated by at least two hours [see Pharmacokinetics (12.3)].
The impact of co-administration of clarithromycin extended-release tablets and zidovudine has not been evaluated.
Calcium Channel Blockers: Verapamil   Use With Caution Verapamil: Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent verapamil, [see Warnings and Precautions (5.4)].
Amlodipine
Diltiazem
  Amlodipine, Diltiazem: [See Warnings and Precautions (5.4)]
Nifedipine   Nifedipine: Nifedipine is a substrate for CYP3A. Clarithromycin and other macrolides are known to inhibit CYP3A. There is potential of CYP3A­-mediated interaction between nifedipine and clarithromycin. Hypotension and peripheral edema were observed when clarithromycin was taken concomitantly with nifedipine [see Warnings and Precautions (5.4)].
Ergot Alkaloids:
Ergotamine
Dihydroergotamine
 Contraindicated Ergotamine, Dihydroergotamine: Postmarketing reports indicate that coadministration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system [see Contraindications (4.6)].
Gastroprokinetic Agents:
Cisapride
 Contraindicated  Cisapride: [See Contraindications (4.2)]
HMG-CoA Reductase Inhibitors:
Lovastatin
Simvastatin
  Contraindicated  Lovastatin, Simvastatin, Atorvastatin, Pravastatin, Fluvastatin: [See Contraindications (4.5) and Warnings and Precautions (5.4)] 
Atorvastatin
Pravastatin
Use With Caution  
Fluvastatin No Dose Adjustment  
Hypoglycemic Agents:
Nateglinide
Pioglitazone
Repaglinide
Rosiglitazone
  Use With Caution Nateglinide, Pioglitazone, Repaglinide, Rosiglitazone: [See Warnings and Precautions (5.4) and Adverse Reactions (6.2)] 
Insulin   Insulin: [See Warnings and Precautions (5.4) and Adverse Reactions (6.2)]
Immunosuppressants:
Cyclosporine
  Use With Caution Cyclosporine: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with cyclosporine.
Tacrolimus   Tacrolimus: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with tacrolimus.
Phosphodiesterase inhibitors:
Sildenafil
Tadalafil
Vardenafil
 Use With Caution Sildenafil, Tadalafil, Vardenafil: Each of these phosphodiesterase inhibitors is primarily metabolized by CYP3A, and CYP3A will be inhibited by concomitant administration of clarithromycin. Co-administration of clarithromycin with sildenafil, tadalafil, or vardenafil will result in increased exposure of these phosphodiesterase inhibitors. Co-administration of these phosphodiesterase inhibitors with clarithromycin is not recommended. Increased systemic exposure of these drugs may occur with clarithromycin; reduction of dosage for phosphodiesterase inhibitors should be considered (see their respective prescribing information).
Proton Pump Inhibitors:
Omeprazole
 No Dose Adjustment Omeprazole: The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when coadministered with clarithromycin as a result of increased omeprazole exposures [see Pharmacokinetics (12.3)] (see also Omeprazole under "Drugs That Affect clarithromycin" in the table below).
Xanthine Derivatives:
Theophylline
 Use With Caution Theophylline: Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serum theophylline concentrations [see Pharmacokinetics (12.3)]. Monitoring of serum theophylline concentrations should be considered for patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range.
Triazolobenzodiazepines and Other Related Benzodiazepines:
Midazolam
   Use With Caution Midazolam: When oral midazolam is co­-administered with clarithromycin, dose adjustments may be necessary and possible prolongation and intensity of effect should be anticipated [see Warnings and Precautions (5.4) and Pharmacokinetics (12.3)].
Alprazolam
Triazolam
  Triazolam, Alprazolam: Caution and appropriate dose adjustments should be considered when triazolam or alprazolam is co-administered with clarithromycin. There have been postmarketing reports of drug interactions and central nervous system (CNS) effects (e.g., somnolence and confusion) with the concomitant use of clarithromycin and triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested.
In postmarketing experience, erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines.
Temazepam
Nitrazepam
Lorazepam
No Dose Adjustment Temazepam, Nitrazepam, Lorazepam: For benzodiazepines which are not metabolized by CYP3A (e.g., temazepam, nitrazepam, lorazepam), a clinically important interaction with clarithromycin is unlikely.
Cytochrome P450 Inducers:
Rifabutin
 Use With Caution Rifabutin: Concomitant administration of rifabutin and clarithromycin resulted in an increase in rifabutin, and decrease in clarithromycin serum levels together with an increased risk of uveitis (see Rifabutin under "Drugs That Affect clarithromycin" in the table below).
Other Drugs Metabolized by CYP3A:
Alfentanil
Bromocriptine
Cilostazol
Methylprednisole
Vinblastine
Phenobarbital
St. John’s Wort
   Use With Caution There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with alfentanil, methylprednisolone, cilostazol, bromocriptine, vinblastine, phenobarbital, and St. John’s Wort.
Other Drugs Metabolized by CYP450 Isoforms Other than CYP3A:
Hexobarbital
Phenytoin
Valproate
   Use With Caution There have been postmarketing reports of interactions of clarithromycin with drugs not thought to be metabolized by CYP3A, including hexobarbital, phenytoin, and valproate.
Drugs that Affect Clarithromycin
Drug(s) that Affect the Pharmacokinetics of Clarithromycin Recommendation Comments
Antifungals:
Itraconazole
 Use With Caution Itraconazole: Itraconazole may increase the plasma concentrations of clarithromycin. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions (see also Itraconazole under "Drugs That Are Affected By clarithromycin" in the table above).
Antivirals:
Atazanavir
  Use With Caution Atazanavir: When clarithromycin is co-administered with atazanavir, the dose of clarithromycin should be decreased by 50% [see Clinical Pharmacology (12.3)].
Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co­- administered with atazanavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium complex. Doses of clarithromycin greater than 1,000 mg per day should not be co-administered with protease inhibitors.
Ritonavir (in patients with decreased renal function)
Saquinavir (in patients with decreased renal function)
  Ritonavir: Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with ritonavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium [see Pharmacokinetics (12.3)].
Doses of clarithromycin greater than 1,000 mg per day should not be co-administered with protease inhibitors.
Saquinavir: When saquinavir is co-administered with ritonavir, consideration should be given to the potential effects of ritonavir on clarithromycin (refer to ritonavir above) [see Pharmacokinetics (12.3)].
Etravirine   Etravirine: Clarithromycin exposure was decreased by etravirine; however, concentrations of the active metabolite, 14-OH-clarithromycin, were increased. Because 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered; therefore alternatives to clarithromycin should be considered for the treatment of MAC.
Saquinavir (in patients with normal renal function)
Ritonavir (in patients with normal renal function)
No Dose Adjustment  
Proton Pump Inhibitors:
Omeprazole
 Use With Caution Omeprazole: Clarithromycin concentrations in the gastric tissue and mucus were also increased by concomitant administration of omeprazole [see Pharmacokinetics (12.3)].
Miscellaneous Cytochrome P450 Inducers:
Efavirenz
Nevirapine
Rifampicin
Rifabutin
Rifapentine
  Use With Caution Inducers of CYP3A enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine will increase the metabolism of clarithromycin, thus decreasing plasma concentrations of clarithromycin, while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. Alternative antibacterial treatment should be considered when treating patients receiving inducers of CYP3A. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with rifabutin (see Rifabutin under "Drugs That Are Affected By clarithromycin" in the table above).


Table name:
Table 1: Drugs that may have their plasma concentrations increased by itraconazole
Drug Class Contraindicated Not Recommended Use with Caution Comments
Under no circumstances is the drug to be coadministered with itraconazole, and up to two weeks after discontinuation of treatment with itraconazole. It is recommended that the use of the drug be avoided during and up to two weeks after discontinuation of treatment with itraconazole, unless the benefits outweigh the potentially increased risks of side effects. If coadministration cannot be avoided, clinical monitoring for signs or symptoms of increased or prolonged effects or side effects of the interacting drug is recommended, and its dosage be reduced or interrupted as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured. The label of the coadministered drug should be consulted for information on dose adjustment and adverse effects. Careful monitoring is recommended when the drug is coadministered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of the interacting drug, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured. The label of the coadministered drug should be consulted for information on dose adjustment and adverse effects.
Alpha Blockers tamsulosin
Analgesics methadone alfentanil,
buprenorphine IV and sublingual,
fentanyl,
oxycodone,
sufentanil
Methadone: The potential increase in plasma concentrations of methadone when coadministered with itraconazole may increase the risk of serious cardiovascular events including QTc prolongation and torsade de pointes.
Fentanyl: The potential increase in plasma concentrations of fentanyl when coadministered with itraconazole may increase the risk of potentially fatal respiratory depression.
Sufentanil: No human pharmacokinetic data of an interaction with itraconazole are available. In vitro data suggest that sufentanil is metabolized by CYP3A4 and so potentially increased sufentanil plasma concentrations would be expected when coadministered with itraconazole.
Antiarrhythmics disopyramide,
dofetilide,
dronedarone,
quinidine
digoxin Disopyramide, dofetilide, dronedarone, quinidine: The potential increase in plasma concentrations of these drugs when coadministered with itraconazole may increase the risk of serious cardiovascular events including QTc prolongation.
Antibacterials telithromycin, in subjects with severe renal impairment or severe hepatic impairment rifabutin telithromycin Telithromycin: The potential increase in plasma concentrations of telithromycin in subjects with severe renal impairment or severe hepatic impairment, when coadministered with itraconazole may increase the risk of serious cardiovascular events including QT prolongation and torsade de pointes.
Rifabutin: See also under ' Drugs that may decrease itraconazole plasma concentrations'.
Anticoagulants and Antiplatelet Drugs ticagrelor apixaban,
rivaroxaban
coumarins,
cilostazol,
dabigatran
Ticagrelor: The potential increase in plasma concentrations of ticagrelor may increase the risk of bleeding.
Coumarins: Itraconazole may enhance the anticoagulant effect of coumarin-like drugs, such as warfarin.
Anticonvulsants carbamazepine Carbamazepine: In vivo studies have demonstrated an increase in plasma carbamazepine concentrations in subjects concomitantly receiving ketoconazole. Although there are no data regarding the effect of itraconazole on carbamazepine metabolism, because of the similarities between ketoconazole and itraconazole, concomitant administration of itraconazole and carbamazepine may inhibit the metabolism of carbamazepine. See also under ' Drugs that may decrease itraconazole plasma concentrations'.
Antidiabetics repaglinide,
saxagliptin
Antihelmintics and Antiprotozoals praziquantel
Antimigraine Drugs ergot alkaloids, such as dihydroergotamine,
ergometrine (ergonovine),
ergotamine,
methylergometrine (methylergonovine)
eletriptan Ergot Alkaloids: The potential increase in plasma concentrations of ergot alkaloids when coadministered with itraconazole may increase the risk of ergotism, ie. a risk for vasospasm potentially leading to cerebral ischemia and/or ischemia of the extremities.
Antineoplastics irinotecan axitinib,
dabrafenib,
dasatinib,
ibrutinib,
nilotinib,
sunitinib,
trabectedin
bortezomib,
busulphan,
docetaxel,
erlotinib,
gefitinib,
imatinib,
ixabepilone,
lapatinib,
ponatinib,
trimetrexate,
vinca alkaloids
Irinotecan: The potential increase in plasma concentrations of irinotecan when coadministered with itraconazole may increase the risk of potentially fatal adverse events.
Antipsychotics, Anxiolytics and Hypnotics lurasidone,
oral midazolam,
pimozide,
triazolam
alprazolam,
aripiprazole,
buspirone,
diazepam,
haloperidol,
midazolam IV,
perospirone,
quetiapine,
ramelteon,
risperidone
Midazolam, triazolam: Coadministration of itraconazole and oral midazolam, or triazolam may cause several-fold increases in plasma concentrations of these drugs. This may potentiate and prolong hypnotic and sedative effects, especially with repeated dosing or chronic administration of these agents.
Pimozide: The potential increase in plasma concentrations of pimozide when coadministered with itraconazole may increase the risk of serious cardiovascular events including QTc prolongation and torsade de pointes.
Antivirals simeprevir maraviroc,
indinavir,
ritonavir,
saquinavir
Indinavir, ritonavir: See also under ' Drugs that may increase itraconazole plasma concentrations'.
Beta Blockers nadolol
Calcium Channel Blockers felodipine,
nisoldipine
other dihydropyridines,
verapamil
Calcium channel blockers can have a negative inotropic effect which may be additive to those of itraconazole. The potential increase in plasma concentrations of calcium channel blockers when co-administered with itraconazole may increase the risk of congestive heart failure. Dihydropyridines: Concomitant administration of itraconazole may cause several-fold increases in plasma concentrations of dihydropyridines. Edema has been reported in patients concomitantly receiving itraconazole and dihydropyridine calcium channel blockers.
Cardiovascular Drugs, Miscellaneous Ivabradine,
ranolazine
aliskiren,
sildenafil, for the treatment of pulmonary hypertension
bosentan,
riociguat
Ivabradine: The potential increase in plasma concentrations of ivabradine when coadministered with itraconazole may increase the risk of ivabradine-related adverse events, such as atrial fibrillation, bradycardia, sinus arrest and heart block.

Ranolazine: The potential increase in plasma concentrations of ranolazine when coadministered with itraconazole may increase the risk of serious cardiovascular events including QTc prolongation.
Diuretics eplerenone Eplerenone: The potential increase in plasma concentrations of eplerenone when coadministered with itraconazole may increase the risk of hyperkalemia and hypotension.
Gastrointestinal Drugs cisapride aprepitant Cisapride: The potential increase in plasma concentrations of cisapride when coadministered with itraconazole may increase the risk of serious cardiovascular events including QTc prolongation.
Immunosuppressants everolimus,
temsirolimus
budesonide,
ciclesonide,
cyclosporine,
dexamethasone,
fluticasone,
methylprednisolone,
rapamycin (also known as sirolimus),
tacrolimus
Lipid Regulating Drugs lovastatin,
simvastatin
atorvastatin The potential increase in plasma concentrations of atorvastatin, lovastatin, and simvastatin when coadministered with itraconazole may increase the risk of skeletal muscle toxicity, including rhabdomyolysis.
Respiratory Drugs salmeterol
Urological Drugs fesoterodine, in subjects with moderate to severe renal impairment, or moderate to severe hepatic impairment,
solifenacin, in subjects with severe renal impairment or moderate to severe hepatic impairment
darifenacin,
vardenafil
fesoterodine.
oxybutynin,
sildenafil, for the treatment of erectile dysfunction,
solifenacin,
tadalafil,
tolterodine
Fesoterodine: The potential increase in plasma concentrations of the fesoterodine active metabolite may be greater in subjects with moderate to severe renal impairment, or moderate to severe hepatic impairment, which may lead to an increased risk of adverse reactions. Solifenacin: The potential increase in plasma concentrations of solifenacin in subjects with severe renal impairment or moderate to severe hepatic impairment, when coadministered with itraconazole may increase the risk of serious cardiovascular events including QT prolongation.
Other colchicine, in subjects with renal or hepatic impairment colchicine,
conivaptan,
tolvaptan
cinacalcet Colchicine: The potential increase in plasma concentrations of colchicine when coadministered with itraconazole may increase the risk of potentially fatal adverse events.
Conivaptan and Tolvaptan: A safe and effective dose of either conivaptan or tolvaptan has not been established when coadministered with itraconazole.


Table name:
Substance Average Duration of Effect
Anti-thyroid drugs
e.g.,
carbimazole, propylthiouracil
 
5 days
Natural or synthetic thyroid hormone
  e.g.,
thyroxine
  tri-iodothyronine
4 weeks
2 weeks
Iodine-containing medications
e.g., amiodarone
expectorants, vitamins
4 weeks
2 weeks
Topical iodide 1-9 months
X-ray contrast agents
iodine-containing agents
 
Up to 1 year
Other drugs
anticoagulants, antihistamines
corticosteroids, sulfonamides
tolbutamide, perchlorate
phenylbutazone
lithium
 
1 week
1 week
1 week
1-2 weeks
4 weeks


Table name:
Table 3Drugs that Can Increase the Risk of Bleeding
Drug  Class
Specific  Drugs
Anticoagulants 
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin 
Antiplatelet Agents 
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine 
Nonsteroidal Anti-Inflammatory Agents 
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac 
Serotonin Reuptake Inhibitors 
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone 


Table name:
Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s) Recommendation Comments
Tizanidine Contraindicated Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)].
Theophylline Avoid Use (Plasma Exposure Likely to be Increased and Prolonged) Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate[see Warnings and Precautions (5.6).]
Drugs Known to Prolong QT Interval Avoid Use Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.10) and Use in Specific Populations (8.5)].
Oral antidiabetic drugs Use with caution Glucose-lowering effect potentiated Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs. [see Adverse Reactions (6.1).]
Phenytoin Use with caution Altered serum levels of phenytoin (increased and decreased) To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after coadministration of ciprofloxacin with phenytoin.
Cyclosporine Use with caution (transient elevations in serum creatinine) Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs Use with caution (Increase in anticoagulant effect) The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole Use with caution Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after coadministration with ciprofloxacin [see Warnings and Precautions (5.15)].
Clozapine Use with caution Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs Use with caution Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil Use with caution 2-fold increase in exposure Monitor for sildenafil toxicity (see Pharmacokinetics -(12.3)-].
Duloxetine Avoid Use 5-fold increase in duloxetine exposure If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products) Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2)]. Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels) Potentiation of ciprofloxacin toxicity may occur.


Table name:
Classes of Drugs
5-lipoxygenase Inhibitor
Adrenergic Stimulants, Central
Alcohol Abuse Reduction
Preparations
Analgesics
Anesthetics, Inhalation
Antiandrogen
Antiarrhythmics†
Antibiotics†
Aminoglycosides (oral)
Cephalosporins, parenteral
Macrolides
Miscellaneous
Penicillins, intravenous,
high dose
Quinolones
(fluoroquinolones)
Sulfonamides, long acting
Tetracyclines
Anticoagulants
Anticonvulsants†
Antidepressants†
Antimalarial Agents
Antineoplastics†
Antiparasitic/Antimicrobials
Antiplatelet Drugs/Effects
Antithyroid Drugs†
Beta-Adrenergic Blockers
Cholelitholytic Agents
Diabetes Agents, Oral
Diuretics†
Fungal Medications,
Intravaginal, Systemic†
Gastric Acidity and Peptic
Ulcer Agents†
Gastrointestinal
Prokinetic Agents
Ulcerative Colitis Agents
Gout Treatment Agents
Hemorrheologic Agents
Hepatotoxic Drugs
Hyperglycemic Agents
Hypertensive Emergency
Agents
Hypnotics†
Hypolipidemics†
Bile Acid-Binding Resins†
Fibric Acid Derivatives
HMG-CoA Reductase
Inhibitors†
Leukotriene Receptor
Antagonist
Monoamine Oxidase
Inhibitors
Narcotics, prolonged
Nonsteroidal Anti-
Inflammatory Agents
Proton Pump Inhibitors
Psychostimulants
Pyrazolones
Salicylates
Selective Serotonin
Reuptake Inhibitors
Steroids, Adrenocortical†
Steroids, Anabolic (17-Alkyl
Testosterone Derivatives)
Thrombolytics
Thyroid Drugs
Tuberculosis Agents†
Uricosuric Agents
Vaccines
Vitamins†


Table name:
Table 1: Clinically Significant Drug Interactions with Morphine Sulfate Extended-Release
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.4)].
Examples: Benzodiazepines and other sedative hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue morphine sulfate extended-release if serotonin syndrome is suspected.
Example: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.6)].
Intervention: Do not use morphine sulfate extended-release in patients taking MAOIs or within 14 days of stopping such treatment.
Examples: phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact: May reduce the analgesic effect of morphine sulfate extended-release and/or precipitate withdrawal symptoms.
Intervention: Avoid concomitant use.
Examples: butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact: Morphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of morphine sulfate extended-release and/or the muscle relaxant as necessary.
Cimetidine
Clinical Impact: The concomitant use of cimetidine can potentiate morphine effects and increase risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of morphine sulfate extended-release and/or cimetidine as necessary.
Diuretics
Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when morphine sulfate extended-release is used concomitantly with anticholinergic drugs.
P-Glycoprotein (P-gp) Inhibitors
Clinical Impact: The concomitant use of PGP-inhibitors can increase the exposure to morphine by about two-fold and can increase risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of morphine sulfate extended-release and/or the PGP-inhibitor as necessary.
Example: quinidine


Table name:
Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
*Change relative to reference
Coadministered Drug
 
Dosing Schedule
Effect on Active Moiety
(Risperidone + 9- Hydroxy-
Risperidone (Ratio*)
Risperidone Dose
Recommendation
Coadministered Drug
Risperidone
AUC
Cmax
Enzyme (CYP2D6)inhibitors
 
 
 
 
Fluoxetine
20 mg/day
2 or 3 mg twice daily
1.4
1.5

Re-evaluate dosing.
Do not exceed 8 mg/day
Paroxetine
10 mg/day
4 mg/day
1.3
-

Re-evaluate dosing.
Do not exceed 8 mg/day
20 mg/day
4 mg/day
1.6
-
40 mg/day
4 mg/day
1.8
-
Enzyme (CYP3A/ PgP inducers) Inducers
 
 
 
 
 
Carbamazepine
573 ± 168 mg/day
 
3 mg twice daily
 
0.51
 
0.55
 

Titrate dose upwards.
Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) inhibitors
 
 
 
 
 
Ranitidine
150 mg twice daily
1 mg single dose
1.2
1.4
Dose adjustment not needed
Cimetidine
400 mg twice daily
1 mg single dose
1.1
1.3
Dose adjustment not needed
Erythromycin
500 mg four times daily
1 mg single dose
1.1
0.94
Dose adjustment not needed
Other Drugs
 
 
 
 
 
Amitriptyline
50 mg twice daily
3 mg twice daily
1.2
1.1
Dose adjustment not Needed


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.12, 7.3)


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T 4 and T 3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
  Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration   Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT 4. Continued administration results in a decrease in serum T 4 and normal FT 4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T 4 and T 3 to TBG and transthyretin. An initial increase in serum FT 4, is followed by return of FT 4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T 4 levels may decrease by as much as 30%.
  Drugs that may alter T 4 and T 3 metabolism
  Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T 4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T 4 to T 3, leading to decreased T 3 levels. However, serum T 4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T 3 and T 4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T 3 concentrations by 30% with minimal change in serum T 4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T 3 and T 4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 7  Summary of AED Interactions with Oxcarbazepine
AED Coadministered Dose of AED (mg/day) Oxcarbazepine Dose  
(mg/day)
Influence of
Oxcarbazepine on AED
Concentration

(Mean Change,

90% Confidence

Interval)
Influence of
AED on MHD

Concentration

(Mean Change,

90% Confidence

Interval)
Carbamazepine 400 to 2000 900 nc1 40% decrease
[CI: 17% decrease,
57% decrease]
Phenobarbital 100 to 150 600 to 1800 14% increase
[CI: 2% increase,
24% increase]
25% decrease
[CI: 12% decrease,
51% decrease]
Phenytoin 250 to 500 600 to 1800
>1200 to 2400
nc1,2
up to 40%
increase3 
[CI: 12% increase,
60% increase]
30% decrease
[CI: 3% decrease,
48% decrease]
Valproic acid 400 to 2800 600 to 1800 nc1 18% decrease
[CI: 13% decrease,
40% decrease]


Table name:
Drugs That Interfere with Hemostasis
Clinical Impact: • Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of VOLTAREN ® GEL with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions ( 5.11)].
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions ( 5.2)].
Intervention: Concomitant use of VOLTAREN ® GEL and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions     ( 5.11)]. VOLTAREN ® GEL is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: • During concomitant use of VOLTAREN ® GEL and ACE-inhibitors, ARBs, or beta- blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of VOLTAREN ® GEL and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions ( 5.6)]. •When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter .
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of VOLTAREN ® GEL with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ see Warnings and Precautions ( 5.6)].
Digoxin
Clinical Impact: The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of VOLTAREN ® GEL and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of VOLTAREN ® GEL and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of VOLTAREN ® GEL and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of VOLTAREN ® GEL and cyclosporine may increase cyclosporine's nephrotoxicity.
Intervention: During concomitant use of VOLTAREN ® GEL and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions ( 5.2)].
Intervention: The concomitant use of diclofenac with other NSAIDs or salicylates is notrecommended.
Pemetrexed
Clinical Impact: Concomitant use of VOLTAREN ® GEL and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of VOLTAREN ® GEL and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and Gl toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 2: Rifabutin Interaction Studies
↑ indicates increase; ↓ indicates decrease; ↔ indicates no significant change
QD-once daily; BID-twice daily; TID – thrice daily
ND -No Data
AUC -Area under the Concentration vs. Time Curve; Cm a x -Maximum serum concentration
a compared to rifabutin 300 mg QD alone
b compared to historical control (fosamprenavir/ritonavir 700/100 mg BID)
c also taking zidovudine 500 mg QD
d compared to rifabutin 150 mg QD alone
e compared to rifabutin 300 mg QD alone
f data from a case report
g compared to voriconazole 200 mg BID alone
Coadministered  drug 
Dosing  regimen  of  coadministered  drug
Dosing  regimen  of  rifabutin
Study  population  ( n )
Effect  on  rifabutin
Effect  on  coadministered  drug
Recommendation
ANTIVIRALS 






Amprenavir 
1200 mg BID x 10 days
300 mg QD x 10 days
Healthy male subjects (6)
↑ AUC by 193%, ↑ Cm a x by 119%

Reduce rifabutin dose by at least 50%. Monitor closely for adverse reactions.
Delavirdine 
400 mg TID
300 mg QD
HIV-infected patients (7)
↑ AUC by 230%, ↑ Cm a x by 128%
↓ AUC by 80%, ↓ Cmax by 75%,
↓ Cm i n by 17%
CONTRAINDICATED
Didanosine 
167 or 250 mg BID x 12 days
300 or 600 mg QD x 1
HIV-infected patients (11)



Fosamprenavir/ ritonavir 
700 mg BID plus ritonavir 100 mg BID x 2 weeks
150 mg every other day x 2 weeks
Healthy subjects (15)
↔ AUCa  ↓ Cm a x by 15%
↑ AUC by 35%b,
↑ Cm a x by 36%, ↑ Cm i n by 36%
Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with fosamprenavir/ritonavir combination.
Indinavir 
800 mg TID x 10 days
300 mg QD x 10 days
Healthy subjects (10)
↑ AUC by 173%, ↑ Cmax by 134%
↓ AUC by 34%, ↓ Cm a x by 25%, ↓ Cm i n by 39%
Reduce rifabutin dose by 50%, and increase indinavir dose from 800 mg to 1000 mg TID.
Lopinavir/
ritonavir 
400/100 mg BID x 20 days
150 mg QD x 10 days
Healthy subjects (14)
↑ AUC by 203%c
↓ Cm a x  by 112%

Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with lopinavir/ritonavir combination. Monitor closely for adverse reactions. Reduce rifabutin dosage further, as needed.
Saquinavir/ ritonavir 
1000/100 mg BID x 14 or 22 days
150 mg every 3 days X 21 to 22 days
Healthy subjects
↑ AUC by 53% d ↑ Cm a x by 88% (n=11)
↓ AUC by 13%, ↓ Cm a x by 15%, (n=19)
Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with saquinavir/ritonavir combination. Monitor closely for adverse reactions.
Ritonavir 
500 mg BID x 10 days
150 mg QD x 16 days
Healthy subjects (5)
↑ AUC by 300%, ↑ Cm a x by 150%
ND
Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with lopinavir/ritonavir combination. Monitor closely for adverse reactions. Reduce rifabutin dosage further, as needed.
Tipranavir/ ritonavir 
500/200 BID X 15 doses
150 mg single dose
Healthy subjects (20)
↑ AUC by 190%, ↑ Cm a x by 70%

Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with tipranavir/ritonavir combination. Monitor closely for adverse reactions. Reduce rifabutin dosage further, as needed.
Nelfinavir 
1250 mg BID x 7 to 8 days
150 mg QD x 8 days
HIV-infected patients (11)
↑ AUC by 83%,e ↑ Cm a x by 19%

Reduce rifabutin dose by 50% (to 150 mg QD) and increase the nelfinavir dose to 1250 mg BID
Zidovudine 
100 or 200 mg q4h
300 or 450 mg QD
HIV-infected patients (16)

↓ AUC by 32%, ↓ Cm a x by 48%
Because zidovudine levels remained within the therapeutic range during coadministration of rifabutin, dosage adjustments are not necessary.
ANTIFUNGALS 



Fluconazole 
200 mg QD x 2 weeks
300 mg QD x 2 weeks
HIV-infected patients (12)
↑ AUC by 82%, ↑ Cm a x by 88%

Monitor for rifabutin associated adverse events. Reduce rifabutin dose or suspend rifabutin use if toxicity is suspected.
Posaconazole 
200 mg QD x 10 days
300 mg QD x 17 days
Healthy subjects (8)
↑ AUC by 72%, ↑ Cm a x by 31%
↓ AUC by 49%, ↓ Cm a x by 43%
If co-administration of these two drugs cannot be avoided, patients should be monitored for adverse events associated with rifabutin administration, and lack of posaconazole efficacy.
Itraconazole 
200 mg QD
300 mg QD
HIV-Infected patients (6)
f
↓ AUC by 70%, ↓ Cm a x by 75%
If co-administration of these two drugs cannot be avoided, patients should be monitored for adverse events associated with rifabutin administration, and lack of itraconazole efficacy. In a separate study, one case of uveitis was associated with increased serum rifabutin levels following coadministration of rifabutin (300 mg QD) with itraconazole (600 to 900 mg QD).
Voriconazole 
400 mg BID x 7 days (maintenance dose)
300 mg QD x 7 days
Healthy male subjects (12)
↑ AUC by 331%, ↑ Cm a x by 195%
↑ AUC by ~100%,
↑ Cm a x by ~100%g
CONTRAINDICATED
ANTI - PCP  ( Pneumocystis  carinii  pneumonia



Dapsone 
50 mg QD
300 mg QD
HIV-infected patients (16)
ND
↓ AUC by 27 to 40%

Sulfamethoxazole-Trimethoprim 
800/160 mg
300 mg QD
HIV-infected patients (12)

↓ AUC by 15 to 20%

ANTI - MAC  ( Mycobacterium  avium  intracellulare  complex
Azithromycin 
500 mg QD x 1 day, then 250 mg QD x 9 days
300 mg QD
Healthy subjects (6)



Clarithromycin 
500 mg BID
300 mg QD
HIV-infected patients (12)
↑ AUC by 75%
↓ AUC by 50%
Monitor for rifabutin associated adverse events. Reduce dose or suspend use of rifabutin if toxicity is suspected. Alternative treatment for clarithromycin should be considered when treating patients receiving rifabutin
ANTI - TB  ( Tuberculosis
Ethambutol 
1200 mg
300 mg QD X 7 days
Healthy subjects (10)
ND


Isoniazid 
300 mg
300 mg QD X 7 days
Healthy subjects (6)
ND


OTHER 
Methadone 
20 to 100 mg QD
300 mg QD X 13 days
HIV-infected patients (24)
ND


Ethinylestradiol (EE)/ Norethindrone (NE) 
35 mg EE / 1 mg NE X 21 days
300 mg QD X 10 days
Healthy female subjects (22)
ND
EE: ↓ AUC by 35%,
↓ Cmax by 20% NE: ↓ AUC by 46%
Patients should be advised to use additional or alternative methods of contraception.
Theophylline 
5 mg/kg
300 mg X 14 days
Healthy subjects (11)
ND




Table name:
Drug/Drug Class (Mechanism of Interaction by Voriconazole) Drug Plasma Exposure (Cmax and AUC τ ) Recommendations for Drug Dosage Adjustment/Comments
Sirolimus* (CYP3A4 Inhibition) Significantly Increased Contraindicated
Rifabutin* (CYP3A4 Inhibition) Significantly Increased Contraindicated
Efavirenz (400 mg q24h)** (CYP3A4 Inhibition)

Efavirenz (300 mg q24h)**
(CYP3A4 Inhibition)
Significantly Increased



Slight Increase in AUCτ
Contraindicated



When voriconazole is coadministered
with efavirenz, voriconazole oral
maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High dose Ritonavir (400 mg q12h)** (CYP3A4 Inhibition)
Low dose Ritonavir (100 mg q12h)**
No Significant Effect of Voriconazole on Ritonavir Cmax or AUCτ
Slight Decrease in Ritonavir Cmax and AUCτ
Contraindicated because of significant reduction of voriconazole Cmax and
AUCτ
Coadministration of voriconazole and low dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole Cmax and AUCτ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids (CYP450 Inhibition) Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Contraindicated
Cyclosporine* (CYP3A4 Inhibition) AUCτ Significantly Increased; No Significant Effect on Cmax When initiating therapy with voriconazole in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When voriconazole is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary
Methadone*** (CYP3A4 Inhibition) Increased Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl (CYP3A4 Inhibition) Increased Reduction in the dose of fentanyl and other long acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate associated adverse events may be necessary [see Drug Interactions (7)].
Alfentanil (CYP3A4 Inhibition) Significantly Increased Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with voriconazole. A longer period for monitoring respiratory and other opiate associated adverse events may be necessary [see Drug Interactions (7)].
Oxycodone (CYP3A4 Inhibition) Significantly Increased Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate associated adverse events may be necessary [see Drug Interactions (7)].
NSAIDs**** including ibuprofen and diclofenac (CYP2C9 Inhibition) Increased Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed [see Drug Interactions (7)].
Tacrolimus* (CYP3A4 Inhibition) Significantly Increased When initiating therapy with voriconazole in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazole is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin* (CYP2C9 Inhibition) Significantly Increased Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)** Increased Monitoring for adverse events related to oral contraceptives is recommended during coadministration.
Warfarin* (CYP2C9 Inhibition) Prothrombin Time Significantly Increased Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed.
Omeprazole* (CYP2C19/3A4 Inhibition) Significantly Increased When initiating therapy with voriconazole in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors (CYP3A4 Inhibition) In Vivo Studies Showed No Significant Effects on Indinavir Exposure

In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)
No dosage adjustment for indinavir when coadministered with voriconazole

Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors
Other NNRTIs***** (CYP3A4 Inhibition) A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to NNRTI
Benzodiazepines (CYP3A4 Inhibition) In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.
HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition) In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition) In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition) Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased
Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed.
Everolimus
(CYP3A4 Inhibition)
Not studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Concomitant administration of voriconazole and everolimus is not recommended.


Table name:
Table 3: Drug Interactions: Pharmacokinetic Parameters for Coadministered Drug in the Presence of Indinavir (See PRECAUTIONS, Table 9 for Recommended Alterations in Dose or Regimen)
Coadministered drug Dose of Coadministered drug (mg) Dose of CRIXIVAN (mg) n Ratio (with/without CRIXIVAN) of Coadministered Drug
Pharmacokinetic Parameters
(90% CI); No Effect = 1.00
Cmax AUC Cmin
All interaction studies conducted in healthy, HIV-negative adult subjects, unless otherwise indicated.
Clarithromycin 500 twice daily,
7 days
800 three times daily, 7 days 12 1.19
(1.02, 1.39)
1.47
(1.30, 1.65)
1.97
(1.58, 2.46)
n=11
Efavirenz 200 once daily,
14 days
800 three times daily, 14 days 20 No significant change No significant change --
Ethinyl Estradiol
(ORTHO-NOVUM 1/35)Registered trademark of Ortho Pharmaceutical Corporation
35 mcg, 8 days 800 three times daily, 8 days 18 1.02
(0.96, 1.09)
1.22
(1.15, 1.30)
1.37
(1.24, 1.51)
Isoniazid 300 once daily in the morning,
8 days
800 three times daily, 8 days 11 1.34
(1.12, 1.60)
1.12
(1.03, 1.22)
1.00
(0.92, 1.08)
MethadoneStudy conducted in subjects on methadone maintenance. 20-60 once daily in the morning,
8 days
800 three times daily, 8 days 12 0.93
(0.84, 1.03)
0.96
(0.86, 1.06)
1.06
(0.94, 1.19)
Norethindrone
(ORTHO-NOVUM 1/35)
1 mcg, 8 days 800 three times daily, 8 days 18 1.05
(0.95, 1.16)
1.26
(1.20, 1.31)
1.44
(1.32, 1.57)
Rifabutin
150 mg once daily in the morning, 11 days + indinavir compared to 300 mg once daily in the morning, 11 days alone
150 once daily in the morning,
10 days

300 once daily in the morning,
10 days
800 three times daily, 10 days


800 three times daily, 10 days
14



10
1.29
(1.05, 1.59)


2.34
(1.64, 3.35)
1.54
(1.33, 1.79)


2.73
(1.99, 3.77)
1.99
(1.71, 2.31)
n=13

3.44
(2.65, 4.46)
n=9
Ritonavir 100 twice daily,
14 days
800 twice daily,
14 days
10, 4Parallel group design; n for coadministered drug + indinavir, n for coadministered drug alone. 1.61
(1.13, 2.29)
1.72
(1.20, 2.48)
1.62
(0.93, 2.85)
200 twice daily,
14 days
800 twice daily,
14 days
9, 5 1.19
(0.85, 1.66)
1.96
(1.39, 2.76)
4.71
(2.66, 8.33)
n=9, 4
Saquinavir
   Hard gel formulation 600 single dose 800 three times daily, 2 days 6 4.7
(2.7, 8.1)
6.0
(4.0, 9.1)
2.9
(1.7, 4.7)C6hr
   Soft gel formulation 800 single dose 800 three times daily, 2 days 6 6.5
(4.7, 9.1)
7.2
(4.3, 11.9)
5.5
(2.2, 14.1)
   Soft gel formulation 1200 single dose 800 three times daily, 2 days 6 4.0
(2.7, 5.9)
4.6
(3.2, 6.7)
5.5
(3.7, 8.3)
Sildenafil 25 single dose 800 three times daily 6 See text below for discussion of interaction.
StavudineStudy conducted in HIV-positive subjects. 40 twice daily,
7 days
800 three times daily, 7 days 13 0.86
(0.73, 1.03)
1.21
(1.09, 1.33)
Not Done
Theophylline 250 single dose (on Days 1 and 7) 800 three times daily, 6 days (Days 2 to 7) 12, 4 0.88
(0.76, 1.03)
1.14
(1.04, 1.24)
1.13
(0.86, 1.49)
n=7, 3
Trimethoprim/
Sulfamethoxazole
   Trimethoprim 800 Trimethoprim/
160 Sulfamethoxazole q12h, 7 days
400 q6h, 7 days 12 1.18
(1.05, 1.32)
1.18
(1.05, 1.33)
1.18
(1.00, 1.39)
Trimethoprim/
Sulfamethoxazole
   Sulfamethoxazole 800 Trimethoprim/
160 Sulfamethoxazole q12h, 7 days
400 q6h, 7 days 12 1.01
(0.95, 1.08)
1.05
(1.01, 1.09)
1.05
(0.97, 1.14)
Vardenafil 10 single dose 800 three times daily 18 See text below for discussion of interaction.
Zidovudine 200 three times daily, 7 days 1000 three times daily, 7 days 12 0.89
(0.73, 1.09)
1.17
(1.07, 1.29)
1.51
(0.71, 3.20)
n=4
Zidovudine/
Lamivudine
   Zidovudine 200/150 three times daily, 7 days 800 three times daily, 7 days 6, 7 1.23
(0.74, 2.03)
1.39
(1.02, 1.89)
1.08
(0.77, 1.50)
n=5, 5
Zidovudine/
Lamivudine
   Lamivudine 200/150 three times daily, 7 days 800 three times daily, 7 days 6, 7 0.73
(0.52, 1.02)
0.91
(0.66, 1.26)
0.88
(0.59, 1.33)


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
 Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration  Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
 Drugs that may alter T 4 and T 3 metabolism
 Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table II. Clinically significant drug interactions with theophylline*.
Drug Type of Interaction Effect**
*Refer to PRECAUTIONS, Drug Interactions for further information regarding table.
**Average effect on steady state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.
Adenosine Theophylline blocks adenosine receptors. Higher doses of adenosine may be required to achieve desired effect.
Alcohol A single large dose of alcohol (3 ml/kg of whiskey) decreases theophylline clearance for up to 24 hours. 30% increase
Allopurinol Decreases theophylline clearance at doses >600 mg/day. 25% increase at allopurinol
Amino glutethimide Increases theophylline clearance by induction of microsomal enzyme activity. 25% decrease
Carbamazepine Similar to aminoglutethimide. 30% decrease
Cimetidine Decreases theophylline clearance by inhibiting cytochrome P450 1A2. 70% increase
Ciprofloxacin Similar to cimetidine. 40% increase
Clarithromycin Similar to erythromycin. 25% increase
Diazepam Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram Decreases theophylline clearance by inhibiting hydroxylation and demethylation. 50% increase
Enoxacin Similar to cimetidine. 300% increase
Ephedrine Synergistic CNS effects Increased frequency of nausea, nervousness, and insomnia.
Erythromycin Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3. 35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen Estrogen containing oral contraceptives decrease theophylline clearance in a dose- dependent fashion. The effect of progesterone on theophylline clearance is unknown. 30% increase
Flurazepam Similar to diazepam. Similar to diazepam.
Fluvoxamine Similar to cimetidine Similar to cimetidine
Halothane Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines. Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-A Decreases theophylline clearance. 100% increase
Isoproterenol (IV) Increases theophylline clearance. 20% decrease
Ketamine Pharmacologic May lower theophylline seizure threshold.
Lithium Theophylline increases renal lithium clearance. Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam Similar to diazepam. Similar to diazepam.
Methotrexate (MTX) Decreases theophylline clearance. 20% increase after low dose MTX, higher dose MTX may have a greater effect.
Mexiletine Similar to disulfiram. 80% increase
Midazolam Similar to diazepam. Similar to diazepam.
Moricizine Increases theophylline clearance. 25% decrease
Pancuronium Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition. Larger dose of pancuronium may be required to achieve neuromuscular blockade.
Pentoxifylline Decreases theophylline clearance. 30% increase
Phenobarbital (PB) Similar to aminoglutethimide. 25% decrease after two weeks of concurrent PB.
Phenytoin Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption. Serum theophylline and phenytoin concentrations decrease about 40%.
Propafenone Decreases theophylline clearance and pharmacologic interaction. 40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Propranolol Similar to cimetidine and pharmacologic interaction. 100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Rifampin Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity. 20-40% decrease
Sulfinpyrazone Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline. 20% decrease
Tacrine Similar to cimetidine, also increases renal clearance of theophylline. 90% increase
Thiabendazole Decreases theophylline clearance. 190% increase
Ticlopidine Decreases theophylline clearance. 60% increase
Troleandomycin Similar to erythromycin. 33-100% increase depending on troleandomycin dose.
Verapamil Similar to disulfiram. 20% increase


Table name:
 Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.12, 7.3)


Table name:
 Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
 Interacting Agents Prescribing
Recommendations
 Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)   Avoid atorvastatin
 HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and
lowest dose
necessary
 Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)

Do not exceed 20
mg atorvastatin
daily
 HIV protease inhibitor (nelfinavir)
 Hepatitis C protease inhibitor (boceprevir)

Do not exceed 40
mg atorvastatin
daily


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7.1, 7.2, 7.3, 7.4)
Interacting Agents Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone Avoid simvastatin
Gemfibrozil, cyclosporine, danazol Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil Do not exceed 20 mg simvastatin daily
Diltiazem Do not exceed 40 mg simvastatin daily
Grapefruit juice Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Drugs That Interfere with Hemostasis
Clinical Impact Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention Monitor patients with concomitant use of diclofenac sodium topical solution with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)] 
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of NSAID alone [see Warnings and Precautions (5.2)] 
Intervention Concomitant use of diclofenac sodium topical solution and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)].

Diclofenac sodium topical solution is not a substitute for low dose aspirin for cardiovascular protection.
ACE inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: During concomitant use of diclofenac sodium topical solution and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of diclofenac sodium topical solution and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)] When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDS reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of diclofenac sodium topical solution with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)]
Digoxin  
Clinical Impact: The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life digoxin.
Intervention: During concomitant use of diclofenac sodium topical solution and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDS have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of diclofenac sodium topical solution and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact; Concomitant use of NSAIDs and methotrexate may increase the risk of methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of diclofenac sodium topical solution and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of diclofenac sodium topical solution and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of diclofenac sodium topical solution and cyclosporine, monitor patients for signs or worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Concomitant use of oral NSAIDs with diclofenac sodium topical solution has been evaluated in one Phase 3 controlled trial and in combination with oral diclofenac, compared to oral diclofenac alone, resulted in a higher rate of rectal hemorrhage (3% vs. less than 1%), and more frequent abnormal creatinine (12% vs. 7%), urea (20% vs. 12%) and hemoglobin (13% vs. 9%).
Intervention: The concomitant use of diclofenac with other NSAIDs or salicyclates is not recommended.
Do not use combination therapy with diclofenac sodium topical solution and an oral NSAID unless the benefit outweighs the risk and conduct periodic laboratory evaluations.
Pemetrexed
Clinical Impact: Concomitant use of diclofenac sodium topical solution and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of diclofenac sodium topical solution and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.
NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration pemetrexed.
In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives 9 e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.


Table name:
 Interacting  Agents 
 Prescribing  Recommendations 
 Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, 
posaconazole, voriconazole, erythromycin, clarithromycin, 
telithromycin, HIV protease inhibitors, boceprevir, telaprevir, 
nefazodone, cobicistatcontaining products), gemfibrozil, 
cyclosporine, danazol 
  Contraindicated with simvastatin 
 Verapamil, diltiazem, dronedarone
 Do not exceed 10 mg simvastatin daily 
 Amiodarone, amlodipine, ranolazine
 Do not exceed 20 mg simvastatin daily 
 Lomitapide
 For patients with HoFH, do not exceed 
20 mg simvastatin dailyFor patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
 Grapefruit juice 
 Avoid grapefruit juice  


Table name:

Figure 6: Mean Standing Systolic Blood Pressure Change from Baseline


Table name:
Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline. Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol,
systemic and inhaled
lomefloxacin
mebendazole
amoxicillin medroxyprogesterone
ampicillin,
with or without sulbactam
methylprednisolone
metronidazole
atenolol metoprolol
azithromycin nadolol
caffeine,
dietary ingestion
nifedipine
nizatidine
cefactor norfloxacin
co-trimoxazole
(trimethoprim and
sulfamethoxazole)
ofloxacin
omeprazole
prednisone, prednisolone
diltiazem ranitidine
dirithromycin rifabutin
enflurane roxithromycin
famotidine sorbitol
felodipine
finasteride
hydrocortisone
  (purgative doses do not
  inhibit theophylline
  absorption)
isoflurane sucralfate
isoniazid terbutaline, systemic
isradipine terfenadine
influenza vaccine tetracycline
ketoconazole tocainide


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.11, 7.3)


Table name:
Table 2: Drug-Thyroidal Axis Interactions
   Drug or Drug Class    Effect
   Drugs that may reduce TSH secretion–the reduction is not sustained; therefore, hypothyroidism does not occur
  Dopamine / Dopamine Agonists
Glucocorticoids
Octreotide
  Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day).
   Drugs that alter thyroid hormone secretion
   Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
  Aminoglutethimide
Amiodarone
Iodide(including iodine-containing
  Radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
  Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients.  The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T 4 and T 3 levels and increase TSH, although all values remain within normal limits in most patients.
   Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
  Amiodarone
Iodide(including iodine-containing   
  Radiographic contrast agents)
  Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma).  Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
   Drugs that may decrease T 4 absorption, which may result in hypothyroidism
  Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
  Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism.  Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents.  Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
   Drugs that may alter T 4 and T 3 serum transport  - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
   Drugs that may increase serum TBG concentration    Drugs that may decrease serum TBG concentration
  Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
  Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
   Drugs that may cause protein-binding site displacement
  Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
  Administration of these agents with levothyroxine results in an initial transient increase in FT 4. Continued administration results in a decrease in serum T 4, and normal FT 4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T 4 and T 3 to TBG and transthyretin. An initial increase in serum FT 4 is followed by return of FT 4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T 4 levels may decrease by as much as 30%.
   Drugs that may alter T 4 and T 3 metabolism
   Drugs that may increase hepatic metabolism, which may result  in hypothyroidism
  Carbamazepine
Hydantoins
Phenobarbital
Rifampin
  Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T 4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
   Drugs that may decrease T 4 5’-deiodinase activity
  Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
  Administration of these enzyme inhibitors decreases the peripheral conversion of T 4 to T 3, leading to decreased T 3 levels. However, serum T 4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T 3 and T 4  levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T 3 concentrations by 30% with minimal change in serum T 4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T 3 and T 4 levels due to decreased TBG production (see above).
   Miscellaneous
  Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
  Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
  Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors
  (SSRIs; e.g., Sertraline)
  Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of  tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
  Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
  Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
  Cardiac Glycosides   Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
  Cytokines
- Interferon-α
- Interleukin-2
  Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
  Growth Hormones
- Somatrem
- Somatropin
  Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
  Ketamine   Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
  Methylxanthine Bronchodilators
- (e.g., Theophylline)
  Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
  Radiographic Agents   Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
  Sympathomimetics   Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
  Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
  These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function.
Drugs that may alter T4 and T3 serum transport - but FT4 concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin/Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens/Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non-Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4 . Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ³ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias
and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123 I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 3Drugs that Can Increase the Risk of Bleeding
Drug  Class
Specific  Drugs
Anticoagulants 
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin 
Antiplatelet Agents 
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine 
Nonsteroidal Anti-Inflammatory Agents 
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac 
Serotonin Reuptake Inhibitors 
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone 


Table name:
Table 1: Clinically Significant Drug Interactions with Morphine Sulfate Oral Solution
 Benzodiazepines and Other Central Nervous System (CNS) Depressants
 Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death.
 Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.5)].
 Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
 Serotonergic Drugs
 Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
 Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment.  Discontinue Morphine Sulfate Oral Solution if serotonin syndrome is suspected.
 Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs),  triptans,  5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs) 
 Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.3, 5.7)]
Intervention:  Do not use Morphine Sulfate Oral Solution in patients taking MAOIs or within 14 days of stopping such treatment. 
Examples:  phenelzine, tranylcypromine, linezolid
 Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
  Clinical Impact:  May reduce the analgesic effect of Morphine Sulfate Oral Solution and/or precipitate withdrawal symptoms.
 Intervention:  Avoid concomitant use.
 Examples:  butorphanol, nalbuphine, pentazocine, buprenorphine,
 Muscle Relaxants
 Clinical Impact: Morphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
 Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Morphine Sulfate Oral Solution and/or the muscle relaxant as necessary.
 Cimetidine 
 Clinical Impact: The concomitant use of morphine and cimetidine has been reported to precipitate apnea, confusion, and muscle twitching in an isolated report.
  Intervention: Monitor patients for increased respiratory and CNS depression when Morphine Sulfate Oral Solution is used concomitantly with cimetidine.
 Diuretics
 Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
  Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
 Anticholinergic Drugs
 Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
  Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when Morphine Sulfate Oral Solution is used concomitantly with anticholinergic drugs.
 P-Glycoprotein (P-gp) Inhibitors
 Clinical Impact: The concomitant use of P-gp inhibitors can increase the exposure to morphine by two-fold and can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
 Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Morphine Sulfate Oral Solution and/or the P-gp inhibitor as necessary.
Examples:  quinidine, verapamil 


Table name:
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin daily*
Grapefruit juice Avoid grapefruit juice


Table name:
Interacting  Drug 
Interaction 
Multivalent cation-containing products including antacids, metal cations or didanosine 
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin 
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents 
Carefully monitor blood glucose (5.12, 7.3)


Table name:
Table 7: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction [See Clinical Pharmacology (12.3) for Magnitude of Interaction, Tables 10 and 11]
Concomitant Drug Class:
Drug Name
Effect on Concentration of Darunavir or Concomitant Drug Clinical Comment
HIV-Antiviral Agents: Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
didanosine ↔ darunavir
↔ didanosine
Didanosine should be administered one hour before or two hours after PREZISTA/ritonavir (which are administered with food).
HIV-Antiviral Agents: HIV-Protease Inhibitors (PIs)
indinavir
 
(The reference regimen for indinavir was indinavir/ritonavir 800/100 mg twice daily.)
↑ darunavir
↑ indinavir
The appropriate dose of indinavir in combination with PREZISTA/ritonavir has not been established.
lopinavir/ritonavir ↓ darunavir
↔ lopinavir
Appropriate doses of the combination have not been established. Hence, it is not recommended to co-administer lopinavir/ritonavir and PREZISTA, with or without ritonavir.
saquinavir ↓ darunavir
↔ saquinavir
Appropriate doses of the combination have not been established. Hence, it is not recommended to co-administer saquinavir and PREZISTA, with or without ritonavir.
HIV-Antiviral Agents: CCR5 co-receptor antagonists
Maraviroc ↑ maraviroc Maraviroc concentrations are increased when co-administered with PREZISTA/rtv. When used in combination with PREZISTA/rtv, the dose of maraviroc should be 150 mg twice daily.
Other Agents
Antiarrhythmics:
bepridil,
lidocaine (systemic),
quinidine,
amiodarone,
flecainide,
propafenone
↑ antiarrhythmics Concentrations of these drugs may be increased when co-administered with PREZISTA/ritonavir. Caution is warranted and therapeutic concentration monitoring, if available, is recommended for antiarrhythmics when co-administered with PREZISTA/ritonavir.
digoxin ↑ digoxin The lowest dose of digoxin should initially be prescribed. The serum digoxin concentrations should be monitored and used for titration of digoxin dose to obtain the desired clinical effect.
Anticoagulant:
warfarin
↓ warfarin
↔ darunavir
Warfarin concentrations are decreased when co-administered with PREZISTA/ritonavir. It is recommended that the international normalized ratio (INR) be monitored when warfarin is combined with PREZISTA/ritonavir.
Anticonvulsant:
carbamazepine
↔ darunavir
↑ carbamazepine
The dose of either darunavir/ritonavir or carbamazepine does not need to be adjusted when initiating co-administration with darunavir/ritonavir and carbamazepine. Clinical monitoring of carbamazepine concentrations and its dose titration is recommended to achieve the desired clinical response.
Anticonvulsant:
phenobarbital,
phenytoin
↔ darunavir
↓ phenytoin
↓ phenobarbital
Co-administration of PREZISTA/ritonavir may cause decrease in the steady-state concentrations of phenytoin and phenobarbital. Phenytoin and phenobarbital levels should be monitored when co-administering with PREZISTA/ritonavir.
Antidepressant:
trazodone,
desipramine
↑ trazodone
↑ desipramine
Concomitant use of trazodone or desipramine and PREZISTA/ritonavir may increase plasma concentrations of trazodone or desipramine which may lead to adverse events such as nausea, dizziness, hypotension and syncope. If trazodone or desipramine is used with PREZISTA/ritonavir, the combination should be used with caution and a lower dose of trazodone or desipramine should be considered.
Anti-infective:
clarithromycin
↔ darunavir
↑ clarithromycin
No dose adjustment of the combination is required for patients with normal renal function. For patients with renal impairment, the following dose adjustments should be considered: For subjects with CLcr of 30-60 mL/min, the dose of clarithromycin should be reduced by 50%. For subjects with CLcr of < 30 mL/min, the dose of clarithromycin should be reduced by 75%.
Antifungals:
ketoconazole,
itraconazole,
voriconazole
↑ ketoconazole
↑ darunavir
↑ itraconazole
(not studied)
↓ voriconazole
(not studied)
Ketoconazole and itraconazole are potent inhibitors as well as substrates of CYP3A. Concomitant systemic use of ketoconazole, itraconazole, and darunavir/ritonavir may increase plasma concentration of darunavir.
Plasma concentrations of ketoconazole or itraconazole may be increased in the presence of darunavir/ritonavir. When co-administration is required, the daily dose of ketoconazole or itraconazole should not exceed 200 mg.
Plasma concentrations of voriconazole may be decreased in the presence of darunavir/ritonavir. Voriconazole should not be administered to patients receiving darunavir/ritonavir unless an assessment of the benefit/risk ratio justifies the use of voriconazole.
Anti-gout:
colchicine
↑ colchicine Treatment of gout-flares – co-administration of colchicine in patients on PREZISTA/ritonavir:
0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Treatment course to be repeated no earlier than 3 days.
 
Prophylaxis of gout-flares – co-administration of colchicine in patients on PREZISTA/ritonavir:
If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.
If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.

Treatment of familial Mediterranean fever – co-administration of colchicine in patients on PREZISTA/ritonavir:
maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Patients with renal or hepatic impairment should not be given colchicine with PREZISTA/ritonavir.
Antimycobacterial:
rifabutin
↑ darunavir
↑ rifabutin
↑ 25-O-desacetylrifabutin
Dose reduction of rifabutin by at least 75% of the usual dose (300 mg once daily) is recommended (i.e., a maximum dose of 150 mg every other day). Increased monitoring for adverse events is warranted in patients receiving this combination and further dose reduction of rifabutin may be necessary.
The reference regimen for rifabutin was 300 mg once daily
β-Blockers:
 
metoprolol,
timolol
↑ beta-blockers Caution is warranted and clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when co-administered with PREZISTA/ritonavir.
Benzodiazepines:
parenterally administered midazolam
↑ midazolam Concomitant use of parenteral midazolam with PREZISTA/ritonavir may increase plasma concentrations of midazolam. Co-administration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Co-administration of oral midazolam with PREZISTA/ritonavir is CONTRAINDICATED.
Calcium Channel
Blockers:
felodipine,
nifedipine,
nicardipine
↑ calcium channel blockers Plasma concentrations of calcium channel blockers (e.g., felodipine, nifedipine, nicardipine) may increase when PREZISTA/ritonavir are co-administered. Caution is warranted and clinical monitoring of patients is recommended.
Corticosteroid:
Systemic:
dexamethasone
↓ darunavir Systemic dexamethasone induces CYP3A and can thereby decrease darunavir plasma concentrations. This may result in loss of therapeutic effect to PREZISTA.
Corticosteroid:
Inhaled/Nasal:
fluticasone
↑ fluticasone Concomitant use of inhaled fluticasone and PREZISTA/ritonavir may increase plasma concentrations of fluticasone. Alternatives should be considered, particularly for long term use.
Endothelin receptor antagonists:
bosentan
↑ bosentan Co-administration of bosentan in patients on PREZISTA/ritonavir:
In patients who have been receiving PREZISTA/ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

Co-administration of PREZISTA/ritonavir in patients on bosentan:
Discontinue use of bosentan at least 36 hours prior to initiation of PREZISTA/ritonavir. After at least 10 days following the initiation of PREZISTA/ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
HMG-CoA
Reductase Inhibitors:
pravastatin,
atorvastatin,
rosuvastatin
↑ pravastatin
↑ atorvastatin
↑ rosuvastatin
Use the lowest possible dose of atorvastatin, pravastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as fluvastatin in combination with PREZISTA/ritonavir.
Immunosuppressants:
cyclosporine,
tacrolimus,
sirolimus
↑ immunosuppressants Plasma concentrations of cyclosporine, tacrolimus or sirolimus may be increased when co-administered with PREZISTA/ritonavir. Therapeutic concentration monitoring of the immunosuppressive agent is recommended when co-administered with PREZISTA/ritonavir.
Inhaled beta agonist:
salmeterol
↑ salmeterol Concurrent administration of salmeterol and PREZISTA/ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Narcotic Analgesic/Treatment of Opioid Dependence:
methadone,
buprenorphine,
buprenorphine/naloxone
↓ methadone
↔ buprenorphine, naloxone
↑ norbuprenorphine (metabolite)
No adjustment of methadone dosage is required when initiating co-administration of PREZISTA/ritonavir. However, clinical monitoring is recommended as the dose of methadone during maintenance therapy may need to be adjusted in some patients.
No dose adjustment for buprenorphine or buprenorphine/naloxone is required with concurrent administration of PREZISTA/ritonavir. Clinical monitoring is recommended if PREZISTA/ritonavir and buprenorphine or buprenorphine/naloxone are coadministered.
Neuroleptics:
risperidone,
thioridazine
↑ neuroleptics A dose decrease may be needed for these drugs when co-administered with PREZISTA/ritonavir.
Oral Contraceptives/estrogen:
ethinyl estradiol,
norethindrone
↓ ethinyl estradiol
↓ norethindrone
Plasma concentrations of ethinyl estradiol are decreased due to induction of its metabolism by ritonavir. Alternative methods of nonhormonal contraception are recommended.
PDE-5 inhibitors:
sildenafil,
vardenafil,
tadalafil
↑ PDE-5 inhibitors (only the use of sildenafil at doses used for treatment of erectile dysfunction has been studied with PREZISTA/ritonavir) Co-administration with PREZISTA/ritonavir may result in an increase in PDE-5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances and priapism.
Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH): Use of sildenafil is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) [see Contraindications (4) ]. The following dose adjustments are recommended for use of tadalafil with PREZISTA/ritonavir:
Co-administration of tadalafil in patients on PREZISTA/ritonavir:
In patients receiving PREZISTA/ritonavir for at least one week, start tadalafil at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.
Co-administration of PREZISTA/ritonavir in patients on tadalafil:
Avoid use of tadalafil during the initiation of PREZISTA/ritonavir. Stop tadalafil at least 24 hours prior to starting PREZISTA/ritonavir. After at least one week following the initiation of PREZISTA/ritonavir, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.
Use of PDE-5 inhibitors for erectile dysfunction:
Sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg dose in 72 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours can be used with increased monitoring for PDE-5 inhibitor-associated adverse events.
Selective Serotonin Reuptake Inhibitors (SSRIs):
sertraline,
paroxetine
↔ darunavir
↓ sertraline
↓ paroxetine
If sertraline or paroxetine is co-administered with PREZISTA/ritonavir, the recommended approach is a careful dose titration of the SSRI based on a clinical assessment of antidepressant response. In addition, patients on a stable dose of sertraline or paroxetine who start treatment with PREZISTA/ritonavir should be monitored for antidepressant response.


Table name:
Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
* Change relative to reference
Coadministered Drug
Dosing Schedule
Effect on Active
Moiety (Risperidone + 9-
Hydroxy- Risperidone (Ratio*)
Risperidone Dose
Recommendation

Coadministered Drug
Risperidone
AUC
Cmax

Enzyme (CYP2D6)
Inhibitors





Fluoxetine
20 mg/day 
2 or 3 mg twice
daily
1.4 
1.5
Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine
10 mg/day 
4 mg/day
1.3
-
Re-evaluate dosing. 

20 mg/day 
4 mg/day
1.6
-
Do not exceed 8 mg/day

40 mg/day 
4 mg/day
1.8
-

Enzyme (CYP3A/ PgP inducers) Inducers





Carbamazepine 
573 ± 168 mg/day
3 mg twice daily
0.51 
0.55
Titrate dose upwards.
Do not exceed twice the patient’s usual dose
Enzyme (CYP3A)
Inhibitors





Ranitidine 
150 mg twice daily
1 mg single dose
1.2 
1.4
Dose adjustment not
needed
Cimetidine 
400 mg twice daily
1 mg single dose
1.1 
1.3
Dose adjustment not
needed
Erythromycin 

500 mg four times
daily
1 mg single dose
1.1 
0.94
Dose adjustment not
needed






Other Drugs





Amitriptyline 
50 mg twice daily
3 mg twice daily
1.2 
1.1
Dose adjustment not
needed


Table name:
AED Coadministered
AED Concentration
Topiramate 
Concentration

a= Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
b= Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated
Phenytoin NC or 25% increasea 48% decrease
Carbamazepine (CBZ) NC 40% decrease
CBZ epoxideb NC NE
Valproic acid 11% decrease 14% decrease
Phenobarbital NC  NE
Primidone NC NE
Lamotrigine NC at TPM doses up to 400 mg/day 13% decrease


Table name:
Interacting Drug Interaction
Theophylline Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin Monitor phenytoin level (7)
Methotrexate Monitor for methotrexate toxicity (7)
Cyclosporine May increase serum creatinine. Monitor serum creatinine (7)
Multivalent cation-containing products including antacids, metal cations or didanosine Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin (7)


Table name:
Increased Risk of Myopathy/Rhabdomyolysis (2, 5.1, 7, 12.3)
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
Lopinavir plus ritonavir Use lowest dose necessary
Clarithromycin, itraconazole,
HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)
Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Table 3. Selected Drugs that altered or are predicted to alter the plasma concentration of itraconazole or have their plasma concentration altered by ONMELThis list is not all-inclusive.
Drug plasma concentration increased by itraconazole
Antiarrhythmics digoxin, dofetilide, quinidine, disopyramide
Anticonvulsants carbamazepine
Anti-HIV Agents indinavir, ritonavir, saquinavir, maraviroc
Antineoplastics busulfan, docetaxel, vinca alkaloids
Antipsychotics pimozide
Benzodiazepines alprazolam, diazepam, midazolam,For information on parenterally administered midazolam, see the Benzodiazepine paragraph below. triazolam
Calcium Channel Blockers dihydropyridines (including nisoldipine and felodipine), verapamil
Gastrointestinal Motility Agents cisapride
HMG CoA-Reductase Inhibitors atorvastatin, cerivastatin, lovastatin, simvastatin
Immunosuppressants Cyclosporine, tacrolimus, sirolimus
Oral Hypoglycemics oral hypoglycemics (repaglinide)
Opiate Analgesics fentanyl, levacetylmethadol (levomethadyl), methadone
Polyene Antifungals amphotericin B
Other ergot alkaloids, halofantrine, alfentanil, buspirone, methylprednisolone, budesonide, dexamethasone, fluticasone, warfarin, cilostazol, eletriptan, fexofenadine, loperamide
   
Decrease plasma concentration of itraconazole
Anticonvulsants carbamazepine, phenobarbital, phenytoin
Anti-HIV Agents nevirapine, efavirenz
Antimycobacterials isoniazid, rifabutin, rifampin
Gastric Acid Suppressors/Neutralizers antacids, H2-receptor antagonists, proton pump inhibitors
   
Increase plasma concentration of itraconazole
Macrolide Antibiotics clarithromycin, erythromycin
Anti-HIV Agents indinavir, ritonavir


Table name:
Table 2: Coagulation Tests Affected and Unaffected by ORBACTIV
Elevated by ORBACTIV Unaffected by ORBACTIV
Prothrombin time (PT) up to 12 hours Chromogenic Factor Xa Assay
International normalized ratio (INR) up to 12 hours Thrombin Time (TT)
Activated partial thromboplastin time (aPTT) up to 120 hours
Activated clotting time (ACT) up to 24 hours
Silica clot time (SCT) up to 18 hours
Dilute Russell’s viper venom time (DRVVT) up to 72 hours
D-dimer up to 72 hours


Table name:
Table 2. Selected Drugs That Have Been Shown To or Are Predicted To Alter The Plasma Concentration Of Ketoconazole
 *This list is not all-inclusive.
 Systemic exposure to ketoconazole is reduced significantly by these drugs: Concomitant use with ketoconazole is not recommended.
 Carbamazepine  Phenytoin
 Gastric Acid Suppressants (antacids, antimuscarinics, histamine H2-blockers, proton pump inhibitors, sucralfate)  Rifampin, rifabutin, isoniazid
 Nevirapine  
  
 Systemic exposure to ketoconazole is increased significantly by this drug: Dose reduction of ketoconazole should be considered
 Ritonavir  


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T 4 and T 3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
  Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration   Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT 4. Continued administration results in a decrease in serum T 4 and normal FT 4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T 4 and T 3 to TBG and transthyretin. An initial increase in serum FT 4, is followed by return of FT 4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T 4 levels may decrease by as much as 30%.
  Drugs that may alter T 4 and T 3 metabolism
  Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T 4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T 4 to T 3, leading to decreased T 3 levels. However, serum T 4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T 3 and T 4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T 3 concentrations by 30% with minimal change in serum T 4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T 3 and T 4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 3: Clinically Significant Drug Interactions with HYSINGLA ER
Inhibitors of CYP3A4
Clinical Impact: The concomitant use of HYSINGLA ER and CYP3A4 inhibitors can increase the plasma concentration of hydrocodone, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of HYSINGLA ER and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of HYSINGLA ER is achieved [see Warnings and Precautions (5.4)].
After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the hydrocodone plasma concentration will decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to hydrocodone.
Intervention: If concomitant use is necessary, consider dosage reduction of HYSINGLA ER until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals.
If a CYP3A4 inhibitor is discontinued, consider increasing the HYSINGLA ER dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
Examples Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)
CYP3A4 Inducers
Clinical Impact: The concomitant use of HYSINGLA ER and CYP3A4 inducers can decrease the plasma concentration of hydrocodone [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to hydrocodone [see Warnings and Precautions (5.4)].
After stopping a CYP3A4 inducer, as the effects of the inducer decline, the hydrocodone plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.
Intervention: If concomitant use is necessary, consider increasing the HYSINGLA ER dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider HYSINGLA ER dosage reduction and monitor for signs of respiratory depression.
Examples: Rifampin, carbamazepine, phenytoin
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.5)].
Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue HYSINGLA ER if serotonin syndrome is suspected.
Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)].
Intervention: The use of HYSINGLA ER is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples: Phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact: May reduce the analgesic effect of HYSINGLA ER and/or precipitate withdrawal symptoms.
Intervention: Avoid concomitant use.
Examples: butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact: Hydrocodone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of HYSINGLA ER and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when HYSINGLA ER is used concomitantly with anticholinergic drugs.
Strong Laxatives
Clinical Impact: Concomitant use of HYSINGLA ER with strong laxatives that rapidly increase gastrointestinal motility, may decrease hydrocodone absorption and result in decreased hydrocodone plasma levels.
Intervention: If HYSINGLA ER is used in these patients, closely monitor for the development of adverse events as well as changing analgesic requirements.
Example: Lactulose


Table name:
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.4)].
Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue hydromorphone hydrochloride extended-release tablets if serotonin syndrome is suspected.
Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.4)].
Intervention: The use of hydromorphone hydrochloride extended-release tablets is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples: phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact: May reduce the analgesic effect of hydromorphone hydrochloride extended-release tablets and/or precipitate withdrawal symptoms [see Warnings and Precautions (5.11)].
Intervention: Avoid concomitant use.
Examples: butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact: Hydromorphone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression [see Warnings and Precautions (5.4)].
Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of hydromorphone hydrochloride extended-release tablets and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when hydromorphone hydrochloride extended-release tablets are used concomitantly with anticholinergic drugs.


Table name:
Table 3Drugs that Can Increase the Risk of Bleeding
Drug  Class
Specific  Drugs
Anticoagulants 
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin 
Antiplatelet Agents 
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine 
Nonsteroidal Anti-Inflammatory Agents 
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac 
Serotonin Reuptake Inhibitors 
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone 


Table name:
Bleeding times
Clinical Impact: Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention: This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact: The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention: Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact: Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention: This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.


Table name:
Table 2: Clinically Significant Drug Interactions with Oxymorphone Hydrochloride Tablets
Alcohol
Clinical Impact: The concomitant use of alcohol with oxymorphone hydrochloride tablets can result in an increase of oxymorphone plasma levels and potentially fatal overdose of oxymorphone.
Intervention: Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products containing alcohol while on oxymorphone hydrochloride tablets therapy [see Clinical Pharmacology (12.3)].
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines and other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.4)].
Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue oxymorphone hydrochloride tablets if serotonin syndrome is suspected.
Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)]. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
Intervention: The use of oxymorphone hydrochloride tablets are not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples: phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact: May reduce the analgesic effect of oxymorphone hydrochloride tablets and/or precipitate withdrawal symptoms.
Intervention: Avoid concomitant use.
Examples: butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact: Oxymorphone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of oxymorphone hydrochloride tablets and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when oxymorphone hydrochloride tablets are used concomitantly with anticholinergic drugs.
Anticholinergic Drugs
Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when oxymorphone hydrochloride tablets are used concomitantly with anticholinergic drugs.
Cimetidine
Clinical Impact: Cimetidine can potentiate opioid-induced respiratory depression.
Intervention: Monitor patients for respiratory depression when oxymorphone hydrochloride tablets and cimetidine are used concurrently.


Table name:
Table 4. Drugs That May Alter Hepatic Metabolism of T4 (Hypothyroidism)
Potential impact: Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased SYNTHROID requirements.
Drug or Drug Class Effect
Phenobarbital
Rifampin
Phenobarbital has been shown to reduce the response to thyroxine. Phenobarbital increases L-thyroxine metabolism by inducing uridine 5’-diphospho-glucuronosyltransferase (UGT) and leads to a lower T4 serum levels. Changes in thyroid status may occur if barbiturates are added or withdrawn from patients being treated for hypothyroidism. Rifampin has been shown to accelerate the metabolism of levothyroxine.


Table name:
Interacting Drug
Interaction
Multivalent cation-containing products including: antacids, sucralfate, multivitamins
Decreased moxifloxacin hydrochloride absorption. Take moxifloxacin hydrochloride tablet at least 4 hours before or 8 hours after these products. (2.2, 7.1, 12.3)
Warfarin
Anticoagulant effect enhanced. Monitor prothrombin time/INR, and bleeding. (6, 7.2, 12.3)
Class IA and Class III antiarrhythmics:
Proarrhythmic effect may be enhanced. Avoid concomitant use. (5.6, 7.5)
Antidiabetic agents
Carefully monitor blood glucose. (5.11, 7.3)


Table name:
Table 7: Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology (12.3)]
Drug/Drug Class
(Mechanism of Interaction by the Drug)
Voriconazole Plasma Exposure
(Cmax and AUCτ after
200 mg q12h)
Recommendations for Voriconazole Dosage Adjustment/Comments
RifampinResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg q12h voriconazole to healthy subjects and Rifabutin
(CYP450 Induction)
Significantly Reduced Contraindicated
Efavirenz (400 mg q24h)Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects
(CYP450 Induction)
Significantly Reduced Contraindicated
Efavirenz (300 mg q24h)
(CYP450 Induction)
Slight Decrease in AUC τ When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h) (CYP450 Induction) Significantly Reduced Contraindicated
Low-dose Ritonavir (100 mg q12h) (CYP450 Induction) Reduced Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Carbamazepine
(CYP450 Induction)
Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction Contraindicated
Long Acting Barbiturates
(CYP450 Induction)
Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction Contraindicated
Phenytoin
(CYP450 Induction)
Significantly Reduced Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg)
St. John's Wort
(CYP450 inducer; P-gp inducer)
Significantly Reduced Contraindicated
Oral Contraceptives
containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)
Increased Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole (CYP2C9, CYP2C19 and CYP3A4 Inhibition) Significantly Increased Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole.
Other HIV Protease Inhibitors
(CYP3A4 Inhibition)
In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir
     
In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors
(CYP3A4 Inhibition or CYP450 Induction)
In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to voriconazole
     
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs
(Decreased Plasma Exposure)
Careful assessment of voriconazole effectiveness


Table name:
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Grapefruit juice Avoid grapefruit juice


Table name:
Interacting Drug Interaction
Valproic acid Doripenem reduced the serum concentrations of valproic acid to below the therapeutic concentration range in healthy subjects (7.1)
Probenecid Reduces renal clearance of doripenem, resulting in increased doripenem concentrations (7.2, 12.3)
Drugs metabolized by cytochrome P450 enzymes Doripenem neither inhibits nor induces major cytochrome P450 enzymes (12.3)


Table name:
Table 1 Changes in Desloratadine and 3-Hydroxydesloratadine Pharmacokinetics in Healthy Male and Female Volunteers
  Desloratadine 3-Hydroxydesloratadine
  Cmax AUC
0–24 hrs
Cmax AUC
0–24 hrs
Erythromycin
(500 mg Q8h)
+24% +14% +43% +40%
Ketoconazole
(200 mg Q12h)
+45% +39% +43% +72%
Azithromycin
(500 mg day 1, 250 mg QD × 4 days)
+15% +5% +15% +4%
Fluoxetine
(20 mg QD)
+15% +0% +17% +13%
Cimetidine
(600 mg Q12h)
+12% +19% -11% -3%


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
↓= Decreased (induces lamotrigine gluronidation).
↑= Increased (inhibits lamotrigine glucuronidation).
?= Conflicting data.
Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine Decreased lamotrigine levels approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? CBZ epoxide May increase CBZ epoxide levels
Phenobarbital/Primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT) ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine Increased lamotrigine concentrations slightly more than 2-fold.
? valproate Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
Factors  
Dosage Adjustments for Aripiprazole  
Known CYP2D6 Poor Metabolizers
Administer half of usual dose
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors
Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors
Administer half of usual dose
Strong CYP2D6 and CYP3A4 inhibitors
Administer a quarter of usual dose
Strong CYP3A4 inducers
Double usual dose over 1 to 2 weeks


Table name:
Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme
Inhibitors
Inducers
CYP2C9 
amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast
aprepitant, bosentan, carbamazepine, phenobarbital, rifampin 
CYP1A2 
acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton
montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking 
CYP3A4 
alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton
armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide 


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
  Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
 Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
 Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)  Avoid atorvastatin
 HIV protease inhibitor (lopinavir plus ritonavir)  Use with caution and lowest dose necessary
 Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir )  Do not exceed 20 mg atorvastatin daily
 HIV protease inhibitor (nelfinavir)  Do not exceed 40 mg atorvastatin daily


Table name:
Table 1: Clinically Significant Drug Interactions with Morphine Sulfate Extended-Release Capsules
Alcohol
Clinical Impact: Concomitant use of alcohol with Morphine Sulfate Extended-Release Capsules can result in an increase of morphine plasma levels and potentially fatal overdose of morphine.
Intervention: Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products containing alcohol while on Morphine Sulfate Extended-Release Capsules therapy [see Clinical Pharmacology (12.3)].
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepine or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.4)].
Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers and muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Morphine Sulfate Extended-Release Capsules if serotonin syndrome is suspected.
Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)].
Intervention: Do not use Morphine Sulfate Extended-Release Capsules in patients taking MAOIs or within 14 days of stopping such treatment.
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact: May reduce the analgesic effect of Morphine Sulfate Extended-Release Capsules and/or precipitate withdrawal symptoms.
Intervention: Avoid concomitant use.
Examples: butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact: Morphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Morphine Sulfate Extended-Release Capsules and/or the muscle relaxant as necessary.
Cimetidine
Clinical Impact: The concomitant use of cimetidine can potentiate morphine effects and increase risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Morphine Sulfate Extended-Release Capsules and/or cimetidine as necessary.
Diuretics
Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when Morphine Sulfate Extended-Release Capsules are used concomitantly with anticholinergic drugs.
P-Glycoprotein (PGP) Inhibitors
Clinical Impact: The concomitant use of PGP-inhibitors can increase the exposure to morphine by about two-fold and can increase risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Morphine Sulfate Extended-Release Capsules and/or the PGP-inhibitor as necessary.


Table name:
Bleeding times
Clinical Impact: Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention: This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact: The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention: Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact: Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention: This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
 Concomitant Drug  Effect on Concentration of Lamotrigine or Concomitant Drug  Clinical Comment
 Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel  ↓ lamotrigine  Decreased lamotrigine levels approximately 50%.
   ↓ levonorgestrel  Decrease in levonorgestrel component by 19%.
 Carbamazepine (CBZ) and CBZ epoxide  ↓ lamotrigine  Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
   ? CBZ epoxide  May increase CBZ epoxide levels
 Phenobarbital/Primidone  ↓ lamotrigine  Decreased lamotrigine concentration approximately 40%.
 Phenytoin (PHT)  ↓ lamotrigine  Decreased lamotrigine concentration approximately 40%.
 Rifampin  ↓ lamotrigine  Decreased lamotrigine AUC approximately 40%.
 Valproate  ↑ lamotrigine  Increased lamotrigine concentrations slightly more than 2-fold.
   ? valproate  Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
 Interacting  Agents 
 Prescribing  Recommendations 
 Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, 
posaconazole, voriconazole, erythromycin, clarithromycin, 
telithromycin, HIV protease inhibitors, boceprevir, telaprevir, 
nefazodone, cobicistatcontaining products), gemfibrozil, 
cyclosporine, danazol 
  Contraindicated with simvastatin 
 Verapamil, diltiazem, dronedarone
 Do not exceed 10 mg simvastatin daily 
 Amiodarone, amlodipine, ranolazine
 Do not exceed 20 mg simvastatin daily 
 Lomitapide
 For patients with HoFH, do not exceed 
20 mg simvastatin dailyFor patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
 Grapefruit juice 
 Avoid grapefruit juice  


Table name:
Table 4: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction [see Clinical Pharmacology (12.3)]
Concomitant Drug Class:
Drug Name
Effect on Concentration of Rilpivirine or Concomitant Drug Clinical Comment
↑ = increase, ↓ = decrease, ↔ = no change
HIV-Antiviral Agents: Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
didanosineThe interaction between EDURANT and the drug was evaluated in a clinical study. All other drug-drug interactions shown are predicted. This interaction study has been performed with a dose higher than the recommended dose for EDURANT assessing the maximal effect on the co-administered drug. The dosing recommendation is applicable to the recommended dose of EDURANT 25 mg once daily. ↔ rilpivirine
↔ didanosine
No dose adjustment is required when EDURANT is co-administered with didanosine. Didanosine is to be administered on an empty stomach and at least two hours before or at least four hours after EDURANT (which should be administered with a meal).
HIV-Antiviral Agents: Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
NNRTI
(delavirdine)
↑ rilpivirine
↔ delavirdine
It is not recommended to co-administer EDURANT with delavirdine and other NNRTIs.

Other NNRTIs
(efavirenz, etravirine, nevirapine)
↓ rilpivirine
↔ other NNRTIs
HIV-Antiviral Agents: Protease Inhibitors (PIs)-Boosted (i.e., with co-administration of low-dose ritonavir) or Unboosted (i.e., without co-administration of low-dose ritonavir)
darunavir/ritonavir ↑ rilpivirine
↔ boosted darunavir
Concomitant use of EDURANT with darunavir/ritonavir may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). No dose adjustment is required when EDURANT is co-administered with darunavir/ritonavir.
lopinavir/ritonavir ↑ rilpivirine
↔ boosted lopinavir
Concomitant use of EDURANT with lopinavir/ritonavir may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). No dose adjustment is required when EDURANT is co-administered with lopinavir/ritonavir.
other boosted PIs (atazanavir/ritonavir, fosamprenavir/ritonavir, saquinavir/ritonavir, tipranavir/ritonavir) ↑ rilpivirine
↔ boosted PI
Concomitant use of EDURANT with boosted PIs may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). EDURANT is not expected to affect the plasma concentrations of co-administered PIs.
unboosted PIs (atazanavir, fosamprenavir, indinavir, nelfinavir) ↑ rilpivirine
↔ unboosted PI
Concomitant use of EDURANT with unboosted PIs may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). EDURANT is not expected to affect the plasma concentrations of co-administered PIs.
Other Agents
Antacids:
antacids (e.g., aluminum or magnesium hydroxide, calcium carbonate)
↔ rilpivirine
(antacids taken at least 2 hours before or at least 4 hours after rilpivirine)

The combination of EDURANT and antacids should be used with caution as co-administration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). Antacids should only be administered either at least 2 hours before or at least 4 hours after EDURANT.

↓ rilpivirine
(concomitant intake)
Antimycobacterials:
rifabutin
↓ rilpivirine Concomitant use of EDURANT with rifabutin may cause a decrease in the plasma concentrations of rilpivirine (induction of CYP3A enzymes). Throughout co-administration of EDURANT with rifabutin, the EDURANT dose should be increased from 25 mg once daily to 50 mg once daily. When rifabutin co-administration is stopped, the EDURANT dose should be decreased to 25 mg once daily.
Azole Antifungal Agents:
fluconazole
itraconazole
ketoconazole
posaconazole
voriconazole
↑ rilpivirine
↓ ketoconazole
Concomitant use of EDURANT with azole antifungal agents may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). No rilpivirine dose adjustment is required when EDURANT is co-administered with azole antifungal agents. Clinically monitor for breakthrough fungal infections when azole antifungals are co-administered with EDURANT.
H2-Receptor Antagonists:
cimetidine
famotidine
nizatidine
ranitidine
↔ rilpivirine
(famotidine taken 12 hours before rilpivirine or 4 hours after rilpivirine)
The combination of EDURANT and H2-receptor antagonists should be used with caution as co-administration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). H2-receptor antagonists should only be administered at least 12 hours before or at least 4 hours after EDURANT.

↓ rilpivirine
(famotidine taken 2 hours before rilpivirine)
Macrolide or ketolide antibiotics:
clarithromycin
erythromycin
telithromycin
↑ rilpivirine
↔ clarithromycin
↔ erythromycin
↔ telithromycin
Concomitant use of EDURANT with clarithromycin, erythromycin or telithromycin may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). Where possible, alternatives such as azithromycin should be considered.
Narcotic Analgesics:
methadone
↓ R(-) methadone
↓ S(+) methadone
No dose adjustments are required when initiating co-administration of methadone with EDURANT. However, clinical monitoring is recommended as methadone maintenance therapy may need to be adjusted in some patients.


Table name:
Table 4: Clinically Relevant Interactions Affecting Omeprazole When Co-Administered with Other Drugs
CYP2C19 or CYP3A4 Inducers
Clinical Impact:
Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology (12.3)].
Intervention:
St. John’s Wort, rifampin: Avoid concomitant use with omeprazole [see Warnings and Precautions (5.9)].
Ritonavir-containing products: see prescribing information for specific drugs.
CYP2C19 or CYP3A4 Inhibitors
Clinical Impact:
Increased exposure of omeprazole [see Clinical Pharmacology (12.3)].
Intervention:
Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered.
 
See prescribing information for voriconazole.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Table 18. Summary of Effect of Co-administered Drugs on Exposure to Active Moiety (Risperidone + 9- Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Co-administered Drug  Dosing Schedule  Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (RatioChange relative to reference Risperidone Dose Recommendation 
  Co-administered Drug  Risperidone  AUC  Cmax   
Enzyme (CYP2D6) Inhibitors           
Fluoxetine  20 mg/day  2 or 3 mg twice daily  1.4  1.5  Re-evaluate dosing. Do not exceed 8 mg/day 
Paroxetine  10 mg/day  4 mg/day  1.3   - Re-evaluate dosing. Do not exceed 8 mg/day
  20 mg/day  4 mg/day  1.6   -   
  40 mg/day  4 mg/day  1.8   -  
Enzyme (CYP3A/PgP inducers) Inducers          
Carbamazepine 573 ± 168 mg/day  3 mg twice daily  0.51 0.55  Titrate dose upwards. Do not exceed twice the patient’s usual dose 
Enzyme (CYP3A) Inhibitors          
Ranitidine  150 mg twice daily  1 mg single dose  1.2  1.4  Dose adjustment not needed 
Cimetidine  400 mg twice daily  1 mg single dose  1.1  1.3  Dose adjustment not needed 
Erythromycin  500 mg four times daily  1 mg single dose  1.1  0.94  Dose adjustment not needed 
Other Drugs           
Amitriptyline  50 mg twice daily  3 mg twice daily  1.2  1.1  Dose adjustment not needed 


Table name:
Drug Name
Effect on Concentration of Nevirapine or Concomitant Drug
Clinical Comment
 
HIV Antiviral Agents: Protease Inhibitors (PIs)
 
Atazanavir/ Ritonavir*
¯ Atazanavir
­ Nevirapine
Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures.
 
Fosamprenavir*
 
¯Amprenavir
­Nevirapine
Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.
 
Fosamprenavir/
Ritonavir*
¯Amprenavir
 
­Nevirapine
No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied.
 
Indinavir*
¯ Indinavir
The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established.
 
Lopinavir/
Ritonavir*
¯Lopinavir
 
Dosing in adult patients:
A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.
 
 
 
Dosing in pediatric patients:
Please refer to the Kaletra® prescribing information for dosing recommendations based on body surface area and body weight.Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.
 
Nelfinavir*
¯Nelfinavir M8 Metabolite
¯Nelfinavir Cmin
The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established.
 
Saquinavir/
Ritonavir
The interaction between nevirapine saquinavir/ritonavir has not been evaluated
The appropriate doses of the combination of and nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
 
Drug Name
 
Effect on Concentration of   Nevirapine or                               Concomitant Drug
 Clinical Comment
 
HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
 
Efavirenz*
¯ Efavirenz
The appropriate doses of these combinations with respect to safety and efficacy have not been established.
 
Delavirdine
Etravirine
Rilpivirine
 
 
Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial.
 
Hepatitis C Antiviral Agents
 
Boceprevir
Plasma concentrations     of boceprevir may be decreased due to induction of CYP3A4/5 by nevirapine
Nevirapine and boceprevir should not be coadministered because decreases in boceprevir plasma concentrations may result in a reduction in efficacy.
 
Telaprevir
Plasma concentrations of telaprevir may be decreased due to induction of CYP3A4 by nevirapine and plasma concentrations of nevirapine may be increased due to inhibition of CYP3A4 by telaprevir.
Nevirapine and telaprevir should not be coadministered because changes in plasma concentrations of nevirapine, telaprevir, or both may be may result in a reduction in telaprevir efficacy or an increase in nevirapine-associated adverse events.
 
Other Agents
 
Analgesics:
Methadone*
¯ Methadone
Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Antiarrhythmics:
Amiodarone,
disopyramide,
 lidocaine
Plasma concentrations may be decreased.
Appropriate doses for this combination have not been established.
Antibiotics:
Clarithromycin*
 ¯ Clarithromycin
­14-OH  clarithromyci
 
Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium aviumintracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.
Rifabutin*
­Rifabutin
Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.
Drug Name
 
Effect on Concentration of Nevirapine or Concomitant Drug
Clinical Comment
Rifampin*
¯ Nevirapine
Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Anticonvulsants:
Carbamazepine,
clonazepam, ethosuximide
Plasma concentrations of nevirapine and the anticonvulsant may be decreased.
Use with caution and monitor virologic response and levels of anticonvulsants.
 
Antifungals: Fluconazole*
­Nevirapine
Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events.
Ketoconazole*
¯ Ketoconazole
Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.
Itraconazole
¯ Itraconazole
Nevirapine and itraconazole should not be administered concomitantly due to potentia
 decreases in itraconazole plasma concentrations that may reduce efficacy of the drug.
Antithrombotics:
Warfarin
Plasma concentrations may be increased.
Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.
Calcium channel
blockers:
Diltiazem,
nifedipine,
verapamil
Plasma concentrations may be decreased.
Appropriate doses for these combinations have not been established.
Cancer chemotherapy:
Cyclophosphamide
Plasma concentrations may be decreased.
Appropriate doses for this combination have not been established.
Ergot alkaloids:
Ergotamine
Plasma concentrations may be decreased.
Appropriate doses for this combination have not been established.
Immunosuppressants: Cyclosporine,
tacrolimus,
sirolimus
Plasma concentrations may be decreased.
Appropriate doses for these combinations have not been established.
Motility agents:
Cisapride
Plasma concentrations may be decreased.
Appropriate doses for this combination have not been established.
Opiate agonists: Fentanyl
Plasma concentrations may be decreased.
Appropriate doses for this combination have not been established.
Oral contraceptives:
Ethinyl estradiol
and Norethindrone*
¯Ethinyl estradiol
¯ Norethindrone
Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended.
* The interaction between nevirapine and the drug was evaluated in a clinical study. All other drug interactions shown are predicted.
 


Table name:
CYP2C19 or CYP3A4 Inducers
Clinical Impact:   Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology (12.3)].
Intervention:   St. John’s Wort, rifampin: Avoid concomitant use with omeprazole [see Warnings and Precautions (5.9)]. Ritonavir-containing products: see prescribing information for specific drugs.
 CYP2C19 or CYP3A4 Inhibitors
Clinical Impact: Increased exposure of omeprazole [see Clinical Pharmacology (12.3)].
Intervention:   Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered. See prescribing information for voriconazole.


Table name:
Summary of AED interactions with topiramate ( 7.1).
AED Co-administered AED Concentration Topiramate Concentration
Phenytoin NC or 25% increase a 48% decrease
Carbamazepine (CBZ) NC 40% decrease
CBZ epoxide b NC NE
Valproic acid 11% decrease 14% decrease
Phenobarbital NC NE
Primidone NC NE
Lamotrigine NC at TPM doses up to 400mg/day 13% decrease


Table name:
Bleeding times
Clinical Impact: Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention: This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact: The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention: Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact: Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention: This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.


Table name:
Table II. Clinically significant drug interactions with theophylline*.
DrugType of InteractionEffect**
*Refer to PRECAUTIONS, Drug Interactions for further information regarding table.
**Average effect on steady state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.
AdenosineTheophylline blocks adenosine receptors.Higher doses of adenosine may be required to achieve desired effect.
AlcoholA single large dose of alcohol (3 ml/kg of whiskey) decreases theophylline clearance for up to 24 hours.30% increase
AllopurinolDecreases theophylline clearance at allopurinol doses >600 mg/day.25% increase
AminoglutethimideIncreases theophylline clearance by induction of microsomal enzyme activity.25% decrease
CarbamazepineSimilar to aminoglutethimide.30% decrease
CimetidineDecreases theophylline clearance by inhibiting cytochrome P450 1A2.70% increase
CiprofloxacinSimilar to cimetidine.40% increase
ClarithromycinSimilar to erythromycin.25% increase
DiazepamBenzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors.Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
DisulfiramDecreases theophylline clearance by inhibiting hydroxylation and demethylation.50% increase
EnoxacinSimilar to cimetidine.300% increase
EphedrineSynergistic CNS effectsIncreased frequency of nausea, nervousness, and insomnia.
ErythromycinErythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3.35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
EstrogenEstrogen containing oral contraceptives decrease theophylline clearance in a dose- dependent fashion. The effect of progesterone on theophylline clearance is unknown.30% increase
FlurazepamSimilar to diazepam.Similar to diazepam.
FluvoxamineSimilar to cimetidineSimilar to cimetidine
HalothaneHalothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines.Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-ADecreases theophylline clearance.100% increase
Isoproterenol (IV)Increases theophylline clearance.20% decrease
KetaminePharmacologicMay lower theophylline seizure threshold.
LithiumTheophylline increases renal lithium clearance.Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
LorazepamSimilar to diazepam.Similar to diazepam.
Methotrexate (MTX)Decreases theophylline clearance.20% increase after low dose MTX, higher dose MTX may have a greater effect.
MexiletineSimilar to disulfiram.80% increase
MidazolamSimilar to diazepam.Similar to diazepam.
MoricizineIncreases theophylline clearance.25% decrease
PancuroniumTheophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition.Larger dose of pancuronium may be required to achieve neuromuscular blockade.
PentoxifyllineDecreases theophylline clearance.30% increase
Phenobarbital (PB)Similar to aminoglutethimide.25% decrease after two weeks of concurrent PB.
PhenytoinPhenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption.Serum theophylline and phenytoin concentrations decrease about 40%.
PropafenoneDecreases theophylline clearance and pharmacologic interaction.40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
PropranololSimilar to cimetidine and pharmacologic interaction.100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
RifampinIncreases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity.20-40% decrease
SulfinpyrazoneIncreases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline.20% decrease
Tacrine Similar to cimetidine, also increases renal clearance of theophylline.90% increase
ThiabendazoleDecreases theophylline clearance.190% increase
TiclopidineDecreases theophylline clearance.60% increase
TroleandomycinSimilar to erythromycin.33-100% increase depending on troleandomycin dose.
VerapamilSimilar to disulfiram.20% increase


Table name:

Figure 5: Mean Standing Systolic Blood Pressure Change from Baseline


Table name:
Digoxin concentrations increased greater than 50%
Digoxin Serum Concentration Increase Digoxin AUC Increase Recommendations
Amiodarone 70% NA Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30% to 50% or by modifying the dosing frequency and continue monitoring.
Captopril 58% 39%
Clarithromycin NA 70%
Dronedarone NA 150%
Gentamicin 129% to 212% NA
Erythromycin 100% NA
Itraconazole 80% NA
Lapatinib NA 180%
Nitrendipine 57% 15%
Propafenone NA 60% to 270%
Quinidine 100% NA
Ranolazine 50% NA
Ritonavir NA 86%
Telaprevir 50% 85%
Tetracycline 100% NA
Verapamil 50% to 75% NA
Digoxin concentrations increased less than 50%
Atorvastatin 22% 15% Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15% to 30% or by modifying the dosing frequency and continue monitoring.
Carvedilol 16% 14%
Conivaptan 33% 43%
Diltiazem 20% NA
Indomethacin 40% NA
Nefazodone 27% 15%
Nifedipine 45% NA
Propantheline 24% 24%
Quinine NA 33%
Rabeprazole 29% 19%
Saquinavir 27% 49%
Spironolactone 25% NA
Telmisartan 20% to 49% NA
Ticagrelor 31% 28%
Tolvaptan 30% NA
Trimethoprim 22% to 28% NA
Digoxin concentrations increased, but magnitude is unclear
Alprazolam, azithromycin, cyclosporine, diclofenac, diphenoxylate, epoprostenol, esomeprazole, ibuprofen, ketoconazole, lansoprazole, metformin, omeprazole Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin concentrations decreased
Acarbose, activated charcoal, albuterol, antacids, certain cancer chemotherapy or radiation therapy, cholestyramine, colestipol, extenatide, kaolin-pectin, meals high in bran, metoclopramide, miglitol, neomycin, penicillamine, phenytoin, rifampin, St. John’s Wort, sucralfate and sulfasalazine Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20% to 40% as necessary.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir ) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Do not exceed 40 mg atorvastatin daily


Table name:
Table II. Clinically significant drug interactions with theophylline*.
Drug Type of Interaction Effect**
*Refer to for further information regarding table. PRECAUTIONS, Drug Interactions
**Average effect on steady state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.
Adenosine Theophylline blocks adenosine receptors. Higher doses of adenosine may be required to achieve desired effect.
Alcohol A single large dose of alcohol (3 ml/kg of whiskey) decreases theophylline clearance for up to 24 hours. 30% increase
Allopurinol Decreases theophylline clearance at allopurinol doses 600 mg/day. > 25% increase
Amino glutethimide Increases theophylline clearance by induction of microsomal enzyme activity. 25% decrease
Carbamazepine Similar to aminoglutethimide. 30% decrease
Cimetidine Decreases theophylline clearance by inhibiting cytochrome P450 1A2. 70% increase
Ciprofloxacin Similar to cimetidine. 40% increase
Clarithromycin Similar to erythromycin. 25% increase
Diazepam Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram Decreases theophylline clearance by inhibiting hydroxylation and demethylation. 50% increase
Enoxacin Similar to cimetidine. 300% increase
Ephedrine Synergistic CNS effects Increased frequency of nausea, nervousness, and insomnia.
Erythromycin Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3. 35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen Estrogen containing oral contraceptives decrease theophylline clearance in a dose- dependent fashion. The effect of progesterone on theophylline clearance is unknown. 30% increase
Flurazepam Similar to diazepam. Similar to diazepam.
Fluvoxamine Similar to cimetidine Similar to cimetidine
Halothane Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines. Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-A Decreases theophylline clearance. 100% increase
Isoproterenol (IV) Increases theophylline clearance. 20% decrease
Ketamine Pharmacologic May lower theophylline seizure threshold.
Lithium Theophylline increases renal lithium clearance. Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam Similar to diazepam. Similar to diazepam.
Methotrexate (MTX) Decreases theophylline clearance. 20% increase after low dose MTX, higher dose MTX may have a greater effect.
Mexiletine Similar to disulfiram. 80% increase
Midazolam Similar to diazepam. Similar to diazepam.
Moricizine Increases theophylline clearance. 25% decrease
Pancuronium Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition. Larger dose of pancuronium may be required to achieve neuromuscular blockade.
Pentoxifylline Decreases theophylline clearance. 30% increase
Phenobarbital (PB) Similar to aminoglutethimide. 25% decrease after two weeks of concurrent PB.
Phenytoin Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption. Serum theophylline and phenytoin concentrations decrease about 40%.
Propafenone Decreases theophylline clearance and pharmacologic interaction. 40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Propranolol Similar to cimetidine and pharmacologic interaction. 100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Rifampin Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity. 20-40% decrease
Sulfinpyrazone Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline. 20% decrease
Tacrine Similar to cimetidine, also increases renal clearance of theophylline. 90% increase
Thiabendazole Decreases theophylline clearance. 190% increase
Ticlopidine Decreases theophylline clearance. 60% increase
Troleandomycin Similar to erythromycin. 33-100% increase depending on troleandomycin dose.
Verapamil Similar to disulfiram. 20% increase


Table name:
AED Coadministered AED Concentration Topiramate Concentration
Phenytoin
NC or 25% increasePlasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
48% decrease


Carbamazepine (CBZ)
NC
40% decrease
CBZ epoxideIs not administered but is an active metabolite of carbamazepine.
NC
NE
Valproic acid
11% decrease
14% decrease
Phenobarbital
NC
NE
Primidone
NC
NE
Lamotrigine
NC at TPM doses up to 400 mg/day
13% decrease


Table name:
Table 3 Clinically Significant Drug Interactions with Meloxicam
Drugs  that  Interfere  with  Hemostasis 
Clinical  Impact
Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. 
Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. 
Intervention

Monitor patients with concomitant use of Meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin 
Clinical  Impact
Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].
Intervention

Concomitant use of Meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. Meloxicam is not a substitute for low dose aspirin for cardiovascular protection.
ACE  Inhibitors Angiotensin  Receptor  Blockers or  Beta - Blockers 
Clinical  Impact
NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). 
In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, coadministration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. 
Intervention

During concomitant use of Meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.  During concomitant use of Meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics 
Clinical  Impact
Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. 
Intervention

During concomitant use of Meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Lithium 
Clinical  Impact
NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [see Clinical Pharmacology (12.3)].
Intervention

During concomitant use of Meloxicam and lithium, monitor patients for signs of lithium toxicity. 
Methotrexate 
Clinical  Impact
Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). 
Intervention

During concomitant use of Meloxicam and methotrexate, monitor patients for methotrexate toxicity. 
Cyclosporine 
Clinical  Impact
Concomitant use of Meloxicam and cyclosporine may increase cyclosporine's nephrotoxicity. 
Intervention

During concomitant use of Meloxicam and cyclosporine, monitor patients for signs of worsening renal function. 
NSAIDs  and  Salicylates 
Clinical  Impact
Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention

The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended. 
Pemetrexed 
Clinical  Impact
Concomitant use of Meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). 
Intervention

During concomitant use of Meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. 

Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. 

In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended. 


Table name:
Table II. Clinically significant drug interactions with theophylline.Refer to PRECAUTIONS, Drug Interactions for further information regarding table.
Drug Type of Interaction EffectAverage effect on steady-state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.
Adenosine Theophylline blocks adenosine receptors. Higher doses of adenosine may be required to achieve desired effect.
Alcohol A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours. 30% increase
Allopurinol Decreases theophylline clearance at allopurinol doses ≥600 mg/day. 25% increase
Aminoglutethimide Increases theophylline clearance by induction of microsomal enzyme activity. 25% decrease
Carbamazepine Similar to aminoglutethimide. 30% decrease
Cimetidine Decreases theophylline clearance by inhibiting cytochrome P450 1A2. 70% increase
Ciprofloxacin Similar to cimetidine. 40% increase
Clarithromycin Similar to erythromycin. 25% increase
Diazepam Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram Decreases theophylline clearance by inhibiting hydroxylation and demethylation. 50% increase
Enoxacin Similar to cimetidine. 300% increase
Ephedrine Synergistic CNS effects Increased frequency of nausea, nervousness, and insomnia.
Erythromycin Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3. 35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown. 30% increase
Flurazepam Similar to diazepam. Similar to diazepam.
Fluvoxamine Similar to cimetidine. Similar to cimetidine.
Halothane Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines. Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-A Decreases theophylline clearance. 100% increase
Isoproterenol (IV) Increase theophylline clearance. 20% increase
Ketamine Pharmacologic May lower theophylline seizure threshold.
Lithium Theophylline increases renal lithium clearance. Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam Similar to diazepam. Similar to diazepam.
Methotrexate (MTX) Decreases theophylline clearance. 20% increase after low dose MTX, higher dose MTX may have a greater effect.
Mexiletine Similar to disulfiram. 80% increase
Midazolam Similar to diazepam. Similar to diazepam.
Moricizine Increases theophylline clearance. 25% decrease
Pancuronium Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition. Larger dose of pancuronium may be required to achieve neuromuscular blockade.
Pentoxifylline Decreases theophylline clearance. 30% increase
Phenobarbital (PB) Similar to aminoglutethimide. 25% decrease after two weeks of concurrent PB.
Phenytoin Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption. Serum theophylline and phenytoin concentrations decrease about 40%.
Propafenone Decreases theophylline clearance and pharmacologic interaction. 40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Propranolol Similar to cimetidine and pharmacologic interaction. 100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Rifampin Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity. 20 to 40% decrease
Sulfinpyrazone Increase theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline. 20% increase
Tacrine Similar to cimetidine, also increases renal clearance of theophylline. 90% increase
Thiabendazole Decreases theophylline clearance. 190% increase
Ticlopidine Decreases theophylline clearance. 60% increase
Troleandomycin Similar to erythromycin. 33 to 100% increase depending on troleandomycin dose.
Verapamil Similar to disulfiram. 20% increase


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T 4 and T 3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT 4. Continued administration results in a decrease in serum T 4 and normal FT 4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T 4 and T 3 to TBG and transthyretin. An initial increase in serum FT 4, is followed by return of FT 4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T 4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T 4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T 4 to T 3, leading to decreased T 3 levels. However, serum T 4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T 3 and T 4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T 3 concentrations by 30% with minimal change in serum T 4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T 3 and T 4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Table 3Drugs that Can Increase the Risk of Bleeding
Drug  Class
Specific  Drugs
Anticoagulants 
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin 
Antiplatelet Agents 
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine 
Nonsteroidal Anti-Inflammatory Agents 
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac 
Serotonin Reuptake Inhibitors 
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone 


Table name:
AED Co-administered
AED Concentration
Topiramate Concentration
Phenytoin
NCor25%increasea
48%decrease
Carbamazepine(CBZ)
NC
40%decrease
CBZepoxideb
NC 
            NE
Valproic acid
11%decrease
14%decrease
Phenobarbital
NC
            NE
Primidone
NC
           NE
Lamotrigine
NCatTPM dosesupto400  mg/day 
         13%decrease


Table name:
Table 18Summary of Effect of Coadministered Drugs on Exposure to Active Moiety(Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients withSchizophrenia
*Change relative to reference
Coadministered Drug Dosing Schedule Effect on Active
Moiety
(Risperidone + 9-
Hydroxy-
Risperidone (Ratio*)
Risperidone Dose
Recommendation
Coadministered Drug Risperidone AUC Cmax
Enzyme (CYP2D6) 
Inhibitors 
Fluoxetine  20 mg/day 2 or 3 mg twice
daily
1.4 1.5 Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine  10 mg/day 4 mg/day 1.3 - Re-evaluate dosing. 
20 mg/day 4 mg/day 1.6 - Do not exceed 8 mg/day
40 mg/day 4 mg/day 1.8 -
Enzyme (CYP3A/ 
PgP inducers) 
Carbamazepine  573 ± 168 mg/day 3 mg twice daily 0.51 0.55 Titrate dose upwards.
Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) 
Inhibitors 
Ranitidine  150 mg twice daily 1 mg single dose 1.2 1.4 Dose adjustment not
needed
Cimetidine  400 mg twice daily 1 mg single dose 1.1 1.3 Dose adjustment not
needed
Erythromycin  500 mg four times
daily
1 mg single dose 1.1 0.94 Dose adjustment not
needed
Other Drugs 
Amitriptyline  50 mg twice daily 3 mg twice daily 1.2 1.1 Dose adjustment not
needed


Table name:
Classes of Drugs
5-lipoxygenase Inhibitor
Adrenergic Stimulants, Central
Alcohol Abuse Reduction
Preparations
Analgesics
Anesthetics, Inhalation
Antiandrogen
Antiarrhythmics†
Antibiotics†
Aminoglycosides (oral)
Cephalosporins, parenteral
Macrolides
Miscellaneous
Penicillins, intravenous,
high dose
Quinolones
(fluoroquinolones)
Sulfonamides, long acting
Tetracyclines
Anticoagulants
Anticonvulsants†
Antidepressants†
Antimalarial Agents
Antineoplastics†
Antiparasitic/Antimicrobials
Antiplatelet Drugs/Effects
Antithyroid Drugs†
Beta-Adrenergic Blockers
Cholelitholytic Agents
Diabetes Agents, Oral
Diuretics†
Fungal Medications,
Intravaginal, Systemic†
Gastric Acidity and Peptic
Ulcer Agents†
Gastrointestinal
Prokinetic Agents
Ulcerative Colitis Agents
Gout Treatment Agents
Hemorrheologic Agents
Hepatotoxic Drugs
Hyperglycemic Agents
Hypertensive Emergency
Agents
Hypnotics†
Hypolipidemics†
Bile Acid-Binding Resins†
Fibric Acid Derivatives
HMG-CoA Reductase
Inhibitors†
Leukotriene Receptor
Antagonist
Monoamine Oxidase
Inhibitors
Narcotics, prolonged
Nonsteroidal Anti-
Inflammatory Agents
Proton Pump Inhibitors
Psychostimulants
Pyrazolones
Salicylates
Selective Serotonin
Reuptake Inhibitors
Steroids, Adrenocortical†
Steroids, Anabolic (17-Alkyl
Testosterone Derivatives)
Thrombolytics
Thyroid Drugs
Tuberculosis Agents†
Uricosuric Agents
Vaccines
Vitamins†


Table name:
Table 4Clinically Relevant Interactions Affecting Omeprazole When Co-Administered with Other Drugs
CYP2C19 or CYP3A4 Inducers

Clinical  Impact :
Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology (12.3)].
Intervention :
St. John’s Wort, rifampin: Avoid concomitant use with omeprazole [see Warnings And Precautions (5.9)]. Ritonavir-containing products: see prescribing information for specific drugs.
CYP2C19  or  CYP3A4  Inhibitors

Clinical  Impact :
Increased exposure of omeprazole [see Clinical Pharmacology (12.3)].
Intervention :
Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered.
See prescribing information for voriconazole.


Table name: FactorsDosage Adjustments for AripirazoleAdminister half of usual doseAdminister a quarter of usual doseStrong CYP2D6 or CYP3A4 inhibitorsAdminister half of usual doseStrong CYP2D6 and CYP3A4 inhibitorsAdminister a quarter of usual doseStrong CYP3A4 inducersDouble usual dose over 1 to 2 weeks
 
 
Known CYP2D6 Poor Metabolizers
 
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors
 
 
 
 
 
 
 


Table name:
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.4)].
Examples: Benzodiazepines and other sedative hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue morphine sulfate extended-release tablets if serotonin syndrome is suspected.
Example: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.6)].
Intervention: Do not use morphine sulfate extended-release tablets in patients taking MAOIs or within 14 days of stopping such treatment.
Examples: phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact: May reduce the analgesic effect of morphine sulfate extended-release tablets and/or precipitate withdrawal symptoms.
Intervention: Avoid concomitant use.
Examples: butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact: Morphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of morphine sulfate extended-release tablets and/or the muscle relaxant as necessary.
Cimetidine
Clinical Impact: The concomitant use of cimetidine can potentiate morphine effects and increase risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of morphine sulfate extended-release tablets and/or cimetidine as necessary.
Diuretics
Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when morphine sulfate extended-release tablets are used concomitantly with anticholinergic drugs.
P-Glycoprotein (P-gp) Inhibitors
Clinical Impact: The concomitant use of PGP-inhibitors can increase the exposure to morphine by about two-fold and can increase risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of morphine sulfate extended-release tablets and/or the PGP-inhibitor as necessary.
Example: quinidine


Table name:
Interacting Drug Interaction
Theophylline Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin Monitor phenytoin level (7)
Methotrexate Monitor for methotrexate toxicity (7)
Cyclosporine May increase serum creatinine. Monitor serum creatinine (7)
Multivalent cation-containing products including antacids, metal cations or didanosine Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin (7)


Table name:
 Interacting Agents  Prescribing Recommendations 
 Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone  Avoid simvastatin 
 Gemfibrozil, cyclosporine,danazol   Do not exceed 10 mg simvastatindaily 
 Amiodarone, verapamil  Do not exceed 20 mg simvastatin daily 
 Diltiazem  Do not exceed 40 mg simvastatin daily
 Grapefruit juice  Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Table 8: Clinically Significant Drug Interactions with BIAXIN
Drugs That Are Affected By BIAXIN
Drug(s) with Pharmacokinetics Affected by BIAXIN Recommendation Comments
Antiarrhythmics:


 
Disopyramide
Quinidine
Dofetilide
Amiodarone
Sotalol
Procainamide
Not Recommended Disopyramide, Quinidine: There have been postmarketing reports of torsades de pointes occurring with concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QTc prolongation during coadministration of clarithromycin with these drugs [see Warnings and Precautions (5.3)].

Serum concentrations of these medications should also be monitored. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with disopyramide and quinidine.

There have been postmarketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide. Therefore, blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide.


Digoxin Use With Caution Digoxin: Digoxin is a substrate for P-glycoprotein (Pgp) and clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are co-administered, inhibition of Pgp by clarithromycin may lead to increased exposure of digoxin. Elevated digoxin serum concentrations in patients receiving clarithromycin and digoxin concomitantly have been reported in postmarketing surveillance. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Monitoring of serum digoxin concentrations should be considered, especially for patients with digoxin concentrations in the upper therapeutic range.


Oral Anticoagulants:


   
Warfarin Use With Caution Oral anticoagulants: Spontaneous reports in the postmarketing period suggest that concomitant administration of clarithromycin and oral anticoagulants may potentiate the effects of the oral anticoagulants. Prothrombin times should be carefully monitored while patients are receiving clarithromycin and oral anticoagulants simultaneously [see Warnings and Precautions (5.4)].


Antiepileptics:


   
Carbamazepine Use With Caution Carbamazepine: Concomitant administration of single doses of clarithromycin and carbamazepine has been shown to result in increased plasma concentrations of carbamazepine. Blood level monitoring of carbamazepine may be considered. Increased serum concentrations of carbamazepine were observed in clinical trials with clarithromycin. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with carbamazepine.


Antifungals:


 
Itraconazole Use With Caution Itraconazole: Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when administered concomitantly (see also Itraconazole under “Drugs That Affect BIAXIN” in the table below). Clarithromycin may increase the plasma concentrations of itraconazole. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions.


Fluconazole No Dose Adjustment

Fluconazole: [see Pharmacokinetics (12.3)]


Anti-Gout Agents:


 
Colchicine (in patients with renal or hepatic impairment)


Contraindicated Colchicine: Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. The dose of colchicine should be reduced when co-administered with clarithromycin in patients with normal renal and hepatic function [see Contraindications (4.4) and Warnings and Precautions (5.4)].


Colchicine (in patients with normal renal and hepatic function) Use With Caution
Antipsychotics:


 
Pimozide Contraindicated Pimozide: [See Contraindications (4.2)]


Quetiapine Quetiapine: Quetiapine is a substrate for CYP3A4, which is inhibited by clarithromycin. Co-administration with clarithromycin could result in increased quetiapine exposure and possible quetiapine related toxicities. There have been postmarketing reports of somnolence, orthostatic hypotension, altered state of consciousness, neuroleptic malignant syndrome, and QT prolongation during concomitant administration. Refer to quetiapine prescribing information for recommendations on dose reduction if co-administered with CYP3A4 inhibitors such as clarithromycin.


Antispasmodics:


   
Tolterodine (patients deficient in CYP2D6 activity) Use With Caution Tolterodine: The primary route of metabolism for tolterodine is via CYP2D6. However, in a subset of the population devoid of CYP2D6, the identified pathway of metabolism is via CYP3A. In this population subset, inhibition of CYP3A results in significantly higher serum concentrations of tolterodine. Tolterodine 1 mg twice daily is recommended in patients deficient in CYP2D6 activity (poor metabolizers) when co-administered with clarithromycin.


Antivirals:


   
Atazanavir Use With Caution Atazanavir: Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction (see Atazanavir under “Drugs That Affect BIAXIN” in the table below) [see Pharmacokinetics (12.3)].


Saquinavir (in patients with decreased renal function)   Saquinavir: Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A and there is evidence of a bi-directional drug interaction (see Saquinavir under “Drugs That Affect BIAXIN” in the table below) [see Pharmacokinetics (12.3)].


Ritonavir
Etravirine
  Ritonavir, Etravirine: (see Ritonavir and Etravirine under “Drugs That Affect BIAXIN” in the table below) [see Pharmacokinetics (12.3)].


Maraviroc   Maraviroc: Clarithromycin may result in increases in maraviroc exposures by inhibition of CYP3A metabolism. See Selzentry® prescribing information for dose recommendation when given with strong CYP3A inhibitors such as clarithromycin.


Boceprevir (in patients with normal renal function)

Didanosine
No Dose Adjustment Boceprevir: Both clarithromycin and boceprevir are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when co-administered. No dose adjustments are necessary for patients with normal renal function (see Victrelis® prescribing information).


Zidovudine   Zidovudine: Simultaneous oral administration of clarithromycin immediate-release tablets and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine concentrations. Administration of clarithromycin and zidovudine should be separated by at least two hours [see Pharmacokinetics (12.3)].

The impact of co-administration of clarithromycin extended-release tablets or granules and zidovudine has not been evaluated.


Calcium Channel Blockers:


   
Verapamil Use With Caution Verapamil: Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent verapamil, [see Warnings and Precautions (5.4)].


Amlodipine
Diltiazem


  Amlodipine, Diltiazem: [See Warnings and Precautions (5.4)]
Nifedipine   Nifedipine: Nifedipine is a substrate for CYP3A. Clarithromycin and other macrolides are known to inhibit CYP3A. There is potential of CYP3A-mediated interaction between nifedipine and clarithromycin. Hypotension and peripheral edema were observed when clarithromycin was taken concomitantly with nifedipine [see Warnings and Precautions (5.4)].


Ergot Alkaloids:


   
Ergotamine
Dihydroergotamine
Contraindicated Ergotamine, Dihydroergotamine: Postmarketing reports indicate that coadministration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system [see Contraindications (4.6)].


Gastroprokinetic Agents:


   
Cisapride Contraindicated Cisapride: [See Contraindications (4.2)]


HMG-CoA Reductase Inhibitors:


   
Lovastatin
Simvastatin
Contraindicated Lovastatin, Simvastatin, Atorvastatin, Pravastatin, Fluvastatin: [See Contraindications (4.5) and Warnings and Precautions (5.4)]


Atorvastatin
Pravastatin


Use With Caution  
Fluvastatin


No Dose Adjustment


 
Hypoglycemic Agents:


   
Nateglinide
Pioglitazone
Repaglinide
Rosiglitazone


Use With Caution Nateglinide, Pioglitazone, Repaglinide, Rosiglitazone: [See Warnings and Precautions (5.4) and Adverse Reactions (6.2)]

Insulin   Insulin: [See Warnings and Precautions (5.4) and Adverse Reactions (6.2)]


Immunosuppressants:


   
Cyclosporine Use With Caution Cyclosporine: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with cyclosporine.


Tacrolimus   Tacrolimus: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with tacrolimus.


Phosphodiesterase inhibitors:


   
Sildenafil
Tadalafil
Vardenafil
Use With Caution Sildenafil, Tadalafil, Vardenafil: Each of these phosphodiesterase inhibitors is primarily metabolized by CYP3A, and CYP3A will be inhibited by concomitant administration of clarithromycin. Co-administration of clarithromycin with sildenafil, tadalafil, or vardenafil will result in increased exposure of these phosphodiesterase inhibitors. Co-administration of these phosphodiesterase inhibitors with clarithromycin is not recommended. Increased systemic exposure of these drugs may occur with clarithromycin; reduction of dosage for phosphodiesterase inhibitors should be considered (see their respective prescribing information).


Proton Pump Inhibitors:


   
Omeprazole No Dose Adjustment Omeprazole: The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when coadministered with clarithromycin as a result of increased omeprazole exposures [see Pharmacokinetics (12.3)] (see also Omeprazole under “Drugs That Affect BIAXIN” in the table below).


Xanthine Derivatives:


   
Theophylline Use With Caution Theophylline: Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serum theophylline concentrations [see Pharmacokinetics (12.3)]. Monitoring of serum theophylline concentrations should be considered for patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range.


Triazolobenzodiazepines and Other Related Benzodiazepines:


   
Midazolam Use With Caution Midazolam: When oral midazolam is co-administered with clarithromycin, dose adjustments may be necessary and possible prolongation and intensity of effect should be anticipated [see Warnings and Precautions (5.4) and Pharmacokinetics (12.3)].


Alprazolam
Triazolam
  Triazolam, Alprazolam: Caution and appropriate dose adjustments should be considered when triazolam or alprazolam is co-administered with clarithromycin. There have been postmarketing reports of drug interactions and central nervous system (CNS) effects (e.g., somnolence and confusion) with the concomitant use of clarithromycin and triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested.

In postmarketing experience, erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines.


Temazepam
Nitrazepam
Lorazepam
No Dose Adjustment Temazepam, Nitrazepam, Lorazepam: For benzodiazepines which are not metabolized by CYP3A (e.g., temazepam, nitrazepam, lorazepam), a clinically important interaction with clarithromycin is unlikely.


Cytochrome P450 Inducers:


   
Rifabutin Use With Caution Rifabutin: Concomitant administration of rifabutin and clarithromycin resulted in an increase in rifabutin, and decrease in clarithromycin serum levels together with an increased risk of uveitis (see Rifabutin under “Drugs That Affect BIAXIN” in the table below).


Other Drugs Metabolized by CYP3A:


   
Alfentanil
Bromocriptine
Cilostazol
Methylprednisole
Vinblastine
Phenobarbital
St. John’s Wort


Use With Caution There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with alfentanil, methylprednisolone, cilostazol, bromocriptine, vinblastine, phenobarbital, and St. John’s Wort.
Other Drugs Metabolized by CYP450 Isoforms Other than CYP3A:


   
Hexobarbital
Phenytoin
Valproate
Use With Caution There have been postmarketing reports of interactions of clarithromycin with drugs not thought to be metabolized by CYP3A, including hexobarbital, phenytoin, and valproate.


Drugs that Affect BIAXIN
Drug(s) that Affect the Pharmacokinetics of BIAXIN Recommendation Comments
Antifungals:


   
Itraconazole

Use With Caution Itraconazole: Itraconazole may increase the plasma concentrations of clarithromycin. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions (see also Itraconazole under “Drugs That Are Affected By BIAXIN” in the table above).


Antivirals:


   
Atazanavir Use With Caution Atazanavir: When clarithromycin is co-administered with atazanavir, the dose of clarithromycin should be decreased by 50% [see Clinical Pharmacology (12.3)].

Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with atazanavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium complex. Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.


Ritonavir (in patients with decreased renal function)   Ritonavir: Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with ritonavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium [see Pharmacokinetics (12.3)].

Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.


Saquinavir (in patients with decreased renal function)   Saquinavir: When saquinavir is co-administered with ritonavir, consideration should be given to the potential effects of ritonavir on clarithromycin (refer to ritonavir above) [see Pharmacokinetics (12.3)].


Etravirine   Etravirine: Clarithromycin exposure was decreased by etravirine; however, concentrations of the active metabolite, 14-OH-clarithromycin, were increased. Because 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered; therefore alternatives to clarithromycin should be considered for the treatment of MAC.


Saquinavir (in patients with normal renal function)


No Dose Adjustment  
Ritonavir (in patients with normal renal function)


   
Proton Pump Inhibitors:


   
Omeprazole Use With Caution Omeprazole: Clarithromycin concentrations in the gastric tissue and mucus were also increased by concomitant administration of omeprazole [see Pharmacokinetics (12.3)].


Miscellaneous Cytochrome P450 Inducers:


 
Efavirenz
Nevirapine
Rifampicin
Rifabutin
Rifapentine
Use With Caution Inducers of CYP3A enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine will increase the metabolism of clarithromycin, thus decreasing plasma concentrations of clarithromycin, while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. Alternative antibacterial treatment should be considered when treating patients receiving inducers of CYP3A. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with rifabutin (see Rifabutin under “Drugs That Are Affected By BIAXIN” in the table above).




Table name:

albuterol, systemic and inhaled

mebendazole

amoxicillin

medroxyprogesterone

ampicillin, with or without

methylprednisolone

sulbactam

metronidazole

atenolol

metoprolol

azithromycin

nadolol

caffeine, dietary ingestion

nifedipine

cefaclor

nizatidine

co-trimoxazole (trimethoprim and

sulfamethoxazole)

norfloxacin

ofloxacin

diltiazem

omeprazole

dirithromycin

prednisone, prednisolone

enflurane

ranitidine

famotidine

rifabutin

felodipine

roxithromycin

finasteride

Sorbitol (purgative doses do not inhibit

hydrocortisone

theophylline absorption)

isoflurane

sucralfate

isoniazid

terbutaline, systemic

isradipine

terfenadine

influenza vaccine

tetracycline

ketoconazole

tocainide

lomefloxacin

 


Table name:
Table 9: Summary of Effect of Coadministered Drugs on Exposure to LATUDA in Healthy Subjects or Patients with Schizophrenia
 Coadministered drug  Dose schedule  Effect on LATUDA pharmacokinetics  Recommendation
   Coadministered drug  LATUDA  C max  AUC  
 Ketoconazole
(strong CYP3A4 inhibitor)
 400 mg/day
for 5 days
 10 mg
single dose
 6.9-times
LATUDA alone
 9-times
LATUDA alone
 Should not be coadministered with LATUDA
 Diltiazem
(moderate CYP3A4 inhibitor)
 240 mg/ day
for 5 days
 20 mg
single dose
 2.1- times
LATUDA alone
 2.2- times
LATUDA alone
 LATUDA dose should not exceed 40 mg/day if coadministered
 Rifampin
(strong CYP3A4 inducer)
 600 mg/day
for 8 days
 40 mg
single dose
 1/7th of LATUDA alone  1/5th of LATUDA alone  Should not be coadministered with LATUDA
 Lithium
 600 mg BID
for 8 days
 120 mg/day
for 8 days
 0.9-times LATUDA alone  1.1- times LATUDA alone  No LATUDA dose adjustment required.


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.11, 7.3)


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine Decreased lamotrigine levels approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? CBZ epoxide May increase CBZ epoxide levels
Phenobarbital/Primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT) ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine Increased lamotrigine concentrations slightly more than 2-fold.
? valproate Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C Protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) Do not exceed 40 mg atorvastatin daily


Table name:
Antibiotics Antineoplastics Antifungals Anti-inflammatory Drugs
ciprofloxacin
gentamicin
tobramycin
vancomycin
trimethoprim with sulfamethoxazole
melphalan amphotericin B
ketoconazole
azapropazon
colchicine
diclofenac
naproxen
sulindac
Gastrointestinal Agents                  Immunosuppressives Other Drugs
cimetidine
ranitidine
               tacrolimus fibric acid derivatives
(e.g. bezafibrate, fenofibrate)
methotrexate


Table name:
Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.*
albuterol, famotidine nizatidine
systemic and inhaled felodipine norfloxacin
amoxicillin finasteride ofloxacin
ampicillin, hydrocortisone omeprazole
with or without isoflurane prednisone, prednisolone
sulbactam isoniazid ranitidine
atenolol isradipine rifabutin
azithromycin influenza vaccine roxithromycin
caffeine, ketoconazole sorbitol
dietary digestion lomefloxacin (purgative doses do not
cefaclor mebendazole inhibit theophylline
co-trimoxazole medroxyprogesterone absorption)
(trimethoprim and methylprednisolone sucralfate
sulfamethoxazole) metronidazole terbutaline, systemic
diltiazem metoprolol terfenadine
dirithromycin nadolol tetracycline
enflurane nifedipine tocainide


Table name:
Drug Interactions Associated with Increased Risk of  Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice Avoid grapefruit juice


Table name:
Table 13 Established and Other Potentially Significant Drug Interactions
Concomitant  Drug
Effect  on  Concentration  of  Lamotrigine  or  Concomitant  Drug
Clinical  Comment
↓ = Decreased (induces lamotrigine glucuronidation)
↑ = Increased (inhibits lamotrigine glucuronidation)
? = Conflicting data
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel
↓ lamotrigine
Decreased lamotrigine levels approximately 50%

↓ levonorgestrel
Decrease in levonorgestrel component by 19%
Carbamazepine (CBZ) and CBZ epoxide
↓ lamotrigine
Addition of carbamazepine decreases lamotrigine concentration approximately 40%

? CBZ epoxide
May increase CBZ epoxide levels.
Phenobarbital/Primidone
↓ lamotrigine
Decreased lamotrigine concentration approximately 40%
Phenytoin (PHT)
↓ lamotrigine
Decreased lamotrigine concentration approximately 40%
Rifampin
↓ lamotrigine
Decreased lamotrigine AUC approximately 40%
Valproate
↑ lamotrigine
Increased lamotrigine concentrations slightly more than 2-fold

? valproate
Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.12, 7.3)


Table name:
 Interacting Agents  Prescribing Recommendations 
 Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, Posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine,danazol  Contraindicated with simvastatin 
 Verapamil, diltiazem  Do not exceed 10 mg simvastatin daily
 Amiodarone, amlodipine, ranolazine   Do not exceed 20 mg simvastatin daily
 Grapefruit juice  Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products ( 2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( 7.2)
Antidiabetic agents Carefully monitor blood glucose ( 5.11, 7.3)


Table name:
Table 4: Clinically Relevant Interactions Affecting Omeprazole When Co-Administered with Other Drugs
CYP2C19 or CYP3A4 Inducers
Clinical Impact:
Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology ( 12.3)].
Intervention:
St. John’s Wort, rifampin: Avoid concomitant use with omeprazole [see Warnings and Precautions ( 5.9)].
Ritonavir-containing products: see prescribing information for specific drugs.
CYP2C19 or CYP3A4 Inhibitors
Clinical Impact:
Increased exposure of omeprazole [see Clinical Pharmacology ( 12.3)].
Intervention:
Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered.
 
See prescribing information for voriconazole.


Table name:
Laboratory Tests Effect of Salicylates
Thyroid Function Decreased PBI; increased T3 uptake
Urinary Sugar False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5 g qd)
5 Hydroxyindole acetic acid False negative with fluorometric test
Acetone, Ketone Bodies False positive FeCl3 in Gerhardt reaction; red color persists with boiling
17-OH corticosteroids False reduced values with >4.8 g qd salicylate
Vanilmandelic Acid False reduced values
Uric Acid May increase or decrease depending on dose
Prothrombin Decreased levels; slightly increased prothrombin time


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
 Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration  Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
 Drugs that may alter T 4 and T 3 metabolism
 Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
 Drugs that Affect Renal Function A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDS], COX-2 inhibitors may impair the excretion of digoxin.
 Antiarrthymics Dofetilide Concomitant administration with digoxin was associated with a higher rate of Torsades de pointes.
Sotalol Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
Dronedarone Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
 Parathyroid Hormone Analog Teriparatide Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
 Thyroid supplement Thyroid Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
 Sympathomimetics Epinephrine Norepinephrine Dopamine Can increase the risk of cardiac arrhythmias.
 Neuromuscular Blocking Agents Succinylcholine May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.
 Supplements Calcium If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
 Beta-adrenergic blockers and  calcium channel blockers Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.


Table name:
Interacting Drug Interaction
   Multivalent cation-containing products
   including antacids, metal cations or didanosine   
   Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)   
   Warfarin
   Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
   Antidiabetic agents
   Carefully monitor blood glucose (5.12, 7.3)


Table name:
Interacting  Drug
Interaction

Multivalent cation-containing products including antacids, metal cation or didanosine


Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. 




Warfarin
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)

Antidiabetic agent

Carefully monitor blood glucose (5.11, 7.3)


Table name:
Classes of Drugs
Adrenal Cortical Steroid Inhibitors Antacids Antianxiety Agents Antiarrhythmics† Antibiotics† Anticonvulsants† Antidepressants† Antihistamines Antineoplastics†








Antipsychotic Medications Antithyroid Drugs† Barbiturates Diuretics† Enteral Nutritional Supplements Fungal Medications, Systemic† Gastric Acidity and Peptic Ulcer Agents† Hypnotics†








Hypolipidemics† Bile Acid-Binding Resins† HMG-CoA Reductase Inhibitors† Immunosuppressives Oral Contraceptives, Estrogen Containing Selective Estrogen Receptor Modulators Steroids, Adrenocortical† Tuberculosis Agents† Vitamins†











Table name:
Table 3 Clinically Significant Drug Interactions with Meloxicam
Drugs that Interfere with Hemostasis
Clinical Impact:

Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:

Monitor patients with concomitant use of MOBIC with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact:

Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].
Intervention:

Concomitant use of MOBIC and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)].

MOBIC is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, or Beta-Blockers
Clinical Impact:

NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:

During concomitant use of MOBIC and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of MOBIC and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:

Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam.
Intervention:

During concomitant use of MOBIC with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Lithium
Clinical Impact:

NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [see Clinical Pharmacology (12.3)].
Intervention:

During concomitant use of MOBIC and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:

Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:

During concomitant use of MOBIC and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:

Concomitant use of MOBIC and cyclosporine may increase cyclosporine's nephrotoxicity.
Intervention:

During concomitant use of MOBIC and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:

Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention:

The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:

Concomitant use of MOBIC and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:

During concomitant use of MOBIC and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.

Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.

In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended.
Kayexalate® (sodium polystyrene sulfonate)
Clinical Impact:

Cases of intestinal necrosis (possibly fatal) have been described in patients who received concomitant sorbitol and Kayexalate® (sodium polystyrene sulfonate). Due to the presence of sorbitol in MOBIC Oral Suspension, use with Kayexalate® is not recommended.
Intervention:

The concomitant use of MOBIC Oral Suspension with Kayexalate® is not recommended.


Table name:
Table 7: Summary of AED Interactions with Oxcarbazepine
AED Coadministered Dose of AED (mg/day) Oxcarbazepine Dose (mg/day) Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval) Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine 400-2000 900 nc nc denotes a mean change of less than 10% 40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital 100-150 600-1800 14% increase [CI: 2% increase, 24% increase] 25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin 250-500 600-1800 >1200-2400 nc Pediatrics up to 40% increase Mean increase in adults at high oxcarbazepine doses [CI: 12% increase, 60% increase] 30% decrease [CI: 3% decrease, 48% decrease]
Valproic acid 400-2800 600-1800 nc 18% decrease [CI: 13% decrease, 40% decrease]


Table name:
Table 3: Clinically Important Drug Interactions with Repaglinide Tablets
Gemfibrozil
Clinical Impact: Gemfibrozil significantly increased repaglinide exposures by 8.1 fold [see Clinical Pharmacology (12.3)].
Intervention: Do not administer repaglinide tablets to patients receiving gemfibrozil [see Contraindications (4)].
Clopidogrel
Clinical Impact: Clopidogrel increased repaglinide exposures by 3.9 to 5.1 fold [see Clinical Pharmacology (12.3)].
Intervention: Avoid concomitant use of repaglinide tablets with clopidogrel. If concomitant use can not be avoided, initiate repaglinide tablets at 0.5 mg before each meal and do not exceed a total daily dose of 4 mg [see Dosage and Administration (2.3)]. Increased frequency of glucose monitoring may be required during concomitant use.
Cyclosporine
Clinical Impact: Cyclosporine increased low dose repaglinide exposures by 2.5 fold [see Clinical Pharmacology (12.3)].
Intervention: Daily maximum repaglinide tablets dose should be limited to 6 mg, and increased frequency of glucose monitoring may be required when repaglinide tablets are co-administered with cyclosporine.
CYP2C8 and CYP3A4 Inhibitors
Intervention: Repaglinide tablets dose reductions and increased frequency of glucose monitoring may be required when co-administered.
Examples: Drugs that are known to inhibit CYP3A4 include antifungal agents (ketoconazole, itraconazole) and antibacterial agents (clarithromycin, erythromycin). Drugs that are known to inhibit CYP2C8 include trimethoprim, gemfibrozil, montelukast, deferasirox, and clopidogrel.
CYP2C8 and CYP3A4 Inducers
Intervention: Repaglinide tablets dose increases and increased frequency of glucose monitoring may be required when co-administered.
Examples: Drugs that induce the CYP3A4 and/or 2C8 enzyme systems include rifampin, barbiturates, and carbamezapine.
Drugs That May Increase the Risk of Hypoglycemia
Intervention: Repaglinide tablets dose reductions and increased frequency of glucose monitoring may be required when co-administered.
Examples: Antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, nonsteroidal anti-inflammatory agents (NSAIDs), pentoxifylline, pramlintide, propoxyphene, salicylates, somatostatin analogs (e.g., octreotide), and sulfonamide antibiotics
Drugs That May Decrease the Blood Glucose Lowering Effect of Repaglinide Tablets
Intervention: Repaglinide tablets dose increases and increased frequency of glucose monitoring may be required when co-administered.
Examples: Atypical antipsychotics (e.g., olanzapine and clozapine), calcium channel antagonists, corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones
Drugs That May Blunt Signs and Symptoms of Hypoglycemia
Intervention: Increased frequency of glucose monitoring may be required when repaglinide tablets are co-administered with these drugs.
Examples: Beta-blockers, clonidine, guanethidine, and reserpine


Table name:
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitors (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Table 18. Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug Dosing Schedule Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (RatioChange relative to reference) Risperidone Dose Recommendation
Coadministered Drug Risperidone AUC Cmax
Enzyme (CYP2D6) Inhibitors
Fluoxetine 20 mg/day 2 or 3 mg twice daily 1.4 1.5 Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine 10 mg/day 4 mg/day 1.3 - Re-evaluate dosing. Do not exceed 8 mg/day
20 mg/day 4 mg/day 1.6 -
40 mg/day 4 mg/day 1.8 -
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine 573 ± 168 mg/day 3 mg twice daily 0.51 0.55 Titrate dose upwards. Do not exceed twice the patient's usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine 150 mg twice daily 1 mg single dose 1.2 1.4 Dose adjustment not needed
Cimetidine 400 mg twice daily 1 mg single dose 1.1 1.3 Dose adjustment not needed
Erythromycin 500 mg four times daily 1 mg single dose 1.1 0.94 Dose adjustment not needed
Other Drugs
Amitriptyline 50 mg twice daily 3 mg twice daily 1.2 1.1 Dose adjustment not needed


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C Protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
*Change relative to reference
Coadministered Drug Dosing Schedule Effect on Active
Moiety
(Risperidone + 9-
Hydroxy-
Risperidone (Ratio*)
Risperidone Dose
Recommendation
Coadministered Drug Risperidone AUC C max
Enzyme (CYP2D6)
Inhibitors
Fluoxetine 20 mg/day 2 or 3 mg twice
daily
1.4 1.5 Re-evaluate dosing. Do not
exceed 8 mg/day
Paroxetine 10 mg/day 4 mg/day 1.3 - Re-evaluate dosing.
20 mg/day 4 mg/day 1.6 - Do not exceed 8 mg/day
40 mg/day 4 mg/day 1.8 -
Enzyme (CYP3A/
PgP inducers)
Carbamazepine 573 ± 168 mg/day 3 mg twice daily 0.51 0.55 Titrate dose upwards.
Do not exceed twice the
patient’s usual dose
Enzyme (CYP3A)
Inhibitors
Ranitidine 150 mg twice daily 1 mg single dose 1.2 1.4 Dose adjustment not
needed
Cimetidine 400 mg twice daily 1 mg single dose 1.1 1.3 Dose adjustment not
needed
Erythromycin 500 mg four times
daily
1 mg single dose 1.1 0.94 Dose adjustment not
needed
Other Drugs
Amitriptyline 50 mg twice daily 3 mg twice daily 1.2 1.1 Dose adjustment not
needed


Table name:
Table 4. Mean (95% C.I.) maximal change in baseline in systolic blood pressure (mmHg) following vardenafil 10 and 20 mg in healthy volunteers on daily alpha-blocker therapy
Dosing of Vardenafil and Alpha-Blocker
Separated by 6 Hours
Simultaneous dosing of Vardenafil
and Alpha-Blocker
Alpha-Blocker Vardenafil 10 mg
Placebo-Subtracted
Vardenafil 20 mg
Placebo-Subtracted
Vardenafil 10 mg
Placebo-Subtracted
Vardenafil 20 mg
Placebo-Subtracted
Terazosin
10 mg daily
Standing SBP -7 (-10, -3) -11 (-14, -7) -23 (-31, 16) Due to the sample size, confidence intervals may not be an accurate measure for these data. These values represent the range for the difference. -14 (-33, 11)
Supine SBP -5 (-8, -2) -7 (-11, -4) -7 (-25, 19) -7 (-31, 22)
Tamsulosin
0.4 mg daily
Standing SBP -4 (-8, -1) -8 (-11, -4) -8 (-14, -2) -8 (-14, -1)
Supine SBP -4 (-8, 0) -7 (-11, -3) -5 (-9, -2) -3 (-7, 0)


Table name:
Interacting Drug Interaction
Theophylline Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin Monitor phenytoin level (7)
Methotrexate Monitor for methotrexate toxicity (7)
Cyclosporine May increase serum creatinine. Monitor serum creatinine (7)
Multivalent cation-containing products including antacids, metal cations or didanosine Decreased Ciprofloxacin Tablets, USP absorption. Take 2 hours before or 6 hours after Ciprofloxacin Tablets, USP (7)


Table name:
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.4)].
Examples: Benzodiazepines and other sedative hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue morphine sulfate extended-release tablets if serotonin syndrome is suspected.
Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.6)].
Intervention: Do not use morphine sulfate extended-release tablets in patients taking MAOIs or within 14 days of stopping such treatment.
Examples: phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact: May reduce the analgesic effect of morphine sulfate extended-release tablets and/or precipitate withdrawal symptoms.
Intervention: Avoid concomitant use.
Examples: butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact: Morphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of morphine sulfate extended-release tablets and/or the muscle relaxant as necessary.
Cimetidine
Clinical Impact: The concomitant use of cimetidine can potentiate morphine effects and increase risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of morphine sulfate extended-release tablets and/or cimetidine as necessary.
Diuretics
Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when morphine sulfate extended-release tablets are used concomitantly with anticholinergic drugs.
P-Glycoprotein (P-gp) Inhibitors
Clinical Impact: The concomitant use of PGP-inhibitors can increase the exposure to morphine by about two-fold and can increase risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of morphine sulfate extended-release tablets and/or the PGP-inhibitor as necessary.
Example: quinidine


Table name:
AED Coadministered AED Concentration Topiramate Concentration
Phenytoin NC or 25% increasea 48% decrease
Carbamazepine (CBZ) NC 40% decrease
CBZ epoxideb NC NE
Valproic acid 11% decrease 14% decrease
Phenobarbital NC NE
Primidone NC NE
Lamotrigine NC at TPM doses up to 400 mg/day 13% decrease


Table name:
Drugs That Interfere with Hemostasis
Clinical Impact: • Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of naproxen or naproxen sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: Concomitant use of naproxen or naproxen sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen or naproxen sodium is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE-inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: • During concomitant use of naproxen or naproxen sodium and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of naproxen or naproxen sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen or naproxen sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact: The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of naproxen or naproxen sodium and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen or naproxen sodium and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of naproxen or naproxen sodium and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of naproxen or naproxen sodium and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of naproxen or naproxen sodium and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of naproxen or naproxen sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of naproxen or naproxen sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact: Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention: Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen or naproxen sodium is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed release tablets are not recommended.
Cholestyramine
Clinical Impact: Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention: Concomitant administration of cholestyramine with naproxen or naproxen sodium is not recommended.
Probenecid
Clinical Impact: Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention: Patients simultaneously receiving naproxen or naproxen sodium and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact: Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention: Patients simultaneously receiving naproxen or naproxen sodium and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.


Table name:
Table 7 Summary of AED Interactions with Oxcarbazepine Tablets
AED Coadministered Dose of AED
(mg/day)
Oxcarbazepine Tablets Dose
(mg/day)
Influence of Oxcarbazepine Tablets on AED Concentration (Mean Change, 90% Confidence Interval) Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
1 nc denotes a mean change of less than 10%
2 Pediatrics
3 Mean increase in adults at high oxcarbazepine tablets doses
Carbamazepine 400-2000 900 nc1 40% decrease [CI:17% decrease, 57% decrease]
Phenobarbital 100-150 600-1800 14% increase [CI: 2% increase, 24% increase] 25% decrease [CI:12% decrease, 51% decrease]
Phenytoin 250-500 600-1800
>1200-2400
nc1,2
up to 40% increase3 [CI: 12% increase, 60% increase]
30% decrease
[CI: 3% decrease, 48% decrease]
Valproic acid 400-2800 600-1800 nc1 18% decrease [CI:13% decrease, 40% decrease]


Table name:
Drugs That Interfere with Hemostasis
Clinical Impact:
Mefenamic acid and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of mefenamic acid and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.
Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:
Monitor patients with concomitant use of mefenamic acid with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity) .
Aspirin
Clinical Impact:
Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation) .
Intervention:
Concomitant use of mefenamic acid and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity).
Mefenamic acid is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:
NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).
In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:
During concomitant use of mefenamic acid and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.
During concomitant use of mefenamic acid and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia).
When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:
Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention
During concomitant use of mefenamic acid with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact:
The concomitant use of mefenamic acid with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:
During concomitant use of mefenamic acid and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:
NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:
During concomitant use of mefenamic acid and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:
Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:
During concomitant use of mefenamic acid and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:
Concomitant use of mefenamic acid and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:
During concomitant use of mefenamic acid and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:
Concomitant use of mefenamic acid with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS;Gastrointestinal Bleeding, Ulceration andPerforation).
Intervention:
The concomitant use of mefenamic acid with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:
Concomitant use of mefenamic acid and pemetrexed may increase the risk of pemetrexed­associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:
During concomitant use of mefenamic acid and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.
NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.
In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacid
Clinical Impact:
In a single dose study (n= 6), ingestion of an antacid containing 1.7-gram of magnesium hydroxide with 500-mg of mefenamic acid increased the C max and AUC of mefenamic acid by 125% and 36%, respectively.
Intervention:
Concomitant use of mefenamic acid and antacids is not generally recommended because of possible increased adverse events.


Table name:

Figure 7: Mean Standing Systolic Blood Pressure Change from Baseline


Table name:
Table 4: Clinically Significant Drug Interactions with ABSTRAL
Inhibitors of CYP3A4
Clinical Impact: The concomitant use of ABSTRAL and CYP3A4 inhibitors can increase the plasma concentration of fentanyl resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of ABSTRAL is achieved [see Warnings and Precautions (5.3)].
After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the fentanyl plasma concentration will decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to fentanyl.
Intervention: If concomitant use is necessary, consider dosage reduction of ABSTRAL until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals.
If a CYP3A4 inhibitor is discontinued, consider increasing the ABSTRAL dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir) grapefruit juice.
CYP3A4 Inducers
Clinical Impact: The concomitant use of ABSTRAL with CYP3A4 inducers can decrease the plasma concentrations of fentanyl [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of withdrawal syndrome in patients who have developed physical dependence to fentanyl [see Warnings and Precautions (5.6)]
After stopping a CYP3A4 inducer, as the effects of the inducer decline, the fentanyl plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.
Intervention: If concomitant use is necessary, consider increasing the ABSTRAL dosage until stable drug effects are achieved Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider ABSTRAL dosage reduction and monitor for signs of respiratory depression.
Examples: rifampin, carbamazepine, phenytoin
Benzodiazepines and other Central Nervous System (CNS) Depressants
Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death.
Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation, [see Warnings and Precautions (5.4)].
Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Warnings and Precautions 5.10].
Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue ABSTRAL if serotonin syndrome is suspected.
Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome [see Warnings and Precautions (5.10)] or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.1)].
Intervention: The use of ABSTRAL is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples: phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact: May reduce the analgesic effect of ABSTRAL and/or precipitate withdrawal symptoms.
Intervention: Avoid concomitant use.
Examples: butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact: Fentanyl may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of ABSTRAL and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention: Monitor patients for signs of diminished diuresis and/or effects on bloodpressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motilitywhen ABSTRAL is used concomitantly with anticholinergic drugs.


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide

Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide






Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T and T levels and increase TSH, although all values remain within normal limits in most patients. 4 3
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate










Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
  Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration   Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen





Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid


Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)





Administration of these agents with levothyroxine results in an initial transient increase in FT . Continued administration results in a decrease in serum T and normal FT and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T and T to TBG and transthyretin. An initial increase in serum FT , is followed by return of FT to normal levels with sustained therapeutic serum salicylate concentrations, although total-T levels may decrease by as much as 30%. 4 4 4 4 3 4 4 4
  Drugs that may alter T 4 and T 3 metabolism
  Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin


Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. 4
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)




Administration of these enzyme inhibitors decrease the peripheral conversion of T to T , leading to decreased T levels. However, serum T levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T and T levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T concentrations by 30% with minimal change in serum T levels. However, long-term glucocorticoid therapy may result in slightly decreased T and T levels due to decreased TBG production (see above). 4 3 3 4 3 4 3 4 3 4
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives

Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)


Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin




Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2

Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin

Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of I, I, and Tc. 123 131 99m
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics









These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
DRUG DESCRIPTION OF INTERACTION
Sulfonylureas Hypoglycemia potentiated.
Methotrexate Decreases tubular reabsorption; clinical toxicity from methotrexate can result.
Oral Anticoagulants Increased bleeding.


Table name: 250 mg (adults weighing at least 60 kg with creatinine clearance of at least 60 mL/min) 200 mg (adults weighing less than 60 kg with creatinine clearance of at least 60 mL/min)Patients should be monitored for didanosine-associated toxicities and clinical response.
Table 5: Established Drug Interactions Based on Studies with VIDEX EC or Studies with Buffered Formulations of Didanosine and Expected to Occur with VIDEX EC
Drug Effect Clinical Comment
↑ Indicates increase.
↓ Indicates decrease.
a  Coadministration of didanosine with food decreases didanosine concentrations. Thus, although not studied, it is possible that coadministration with heavier meals could reduce didanosine concentrations further.
ganciclovir ↑ didanosine concentration If there is no suitable alternative to ganciclovir, then use in combination with VIDEX EC with caution. Monitor for didanosine-associated toxicity.
methadone ↓ didanosine concentration If coadministration of methadone and didanosine is necessary, the recommended formulation of didanosine is VIDEX EC. Patients should be closely monitored for adequate clinical response when VIDEX EC is coadministered with methadone, including monitoring for changes in HIV RNA viral load. Do not coadminister methadone with VIDEX pediatric powder due to significant decreases in didanosine concentrations.
nelfinavir No interaction 1 hour after didanosine Administer nelfinavir 1 hour after VIDEX EC.
tenofovir disoproxil fumarate ↑ didanosine concentration A dose reduction of VIDEX EC to the following dosage once daily taken together with tenofovir disoproxil fumarate and a light meal (400 kcalories or less and 20% fat or less) or in the fasted state is recommended.a


Table name:
Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
*Change relative to reference
Coadministered Drug Dosing Schedule Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio*) Risperidone Dose Recommendation
Coadministered Drug Risperidone AUC Cmax
Enzyme (CYP2D6) Inhibitors
Fluoxetine 20 mg/day 2 or 3 mg twice daily 1.4 1.5 Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine 10 mg/day 4 mg/day 1.3 - Re-evaluate dosing. Do not exceed 8 mg/day
20 mg/day 4 mg/day 1.6 -
40 mg/day 4 mg/day 1.8 -
Enzyme (CYP3A/PgP inducers) Inducers
Carbamazepine 573 ± 168 mg/day 3 mg twice daily 0.51 0.55 Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine 150 mg twice daily 1 mg single dose 1.2 1.4 Dose adjustment not needed
Cimetidine 400 mg twice daily 1 mg single dose 1.1 1.3 Dose adjustment not needed
Erythromycin 500 mg four times daily 1 mg single dose 1.1 0.94 Dose adjustment not needed
Other Drugs
Amitriptyline 50 mg twice daily 3 mg twice daily 1.2 1.1 Dose adjustment not needed


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cation or didanosine Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products.
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agent Carefully monitor blood glucose (5.11, 7.3)


Table name:
Table 14: Clinically Important Drug Interactions: Effect of other Drugs on Guanfacine Extended-Release
 Concomitant Drug Name or
Drug Class
 Clinical Rationale and Magnitude of Drug Interaction  Clinical Recommendation
 Strong and moderate CYP3A4 inhibitors, e.g., ketoconazole, fluconazole  Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected
resulting in an increase in exposure
 Consider dose reduction [see Dosage and administration ( 2.7 )]
 Strong and moderate CYP3A4 inducers, e.g., rifampin, efavirenz  Guanfacine is primarily metabolized by CYP3A4 and its
plasma concentrations can be significantly affected resulting in a decrease in exposure
 Consider dose increase
[see Dosage and administration ( 2.7 )]


Table name:
Table 3       Effects of Other Drugs on Paroxetine
Concomitant
Drug Name


Effect of Concomitant Drug
on Paroxetine


Clinical Recommendations

Phenobarbital

Decreased paroxetine exposure
 


Phenytoin

Decreased paroxetine exposure

 


Fosamprenavir/
Ritonavir


Decreased plasma concentration
of paroxetine
No dose adjustment for BRISDELLE.

Monitor clinical effect of BRISDELLE.
Cimetidine Increased plasma concentration
of paroxetine

 


Table name:
CYP3A Inhibitors
 
Clinical Impact 
Paricalcitol is partially metabolized by CYP3A. Hence, exposure of paricalcitol will increase upon coadministration with strong CYP3A inhibitors such as but not limited to: boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir,  itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole.
Intervention
Dose adjustment of Paricalcitol capsules may be necessary. Monitor closely for iPTH and serum calcium concentrations, if a  patient initiates or discontinues therapy with a strong CYP3A4 inhibitor.
Cholestyramine
 
Clinical Impact  
Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of paricalcitol.
Intervention  
Recommend to take Paricalcitol capsules at least 1 hour before or 4 to 6 hours after taking cholestyramine (or at as great an interval as possible) to avoid impeding absorption of paricalcitol.
Mineral Oil
 
Clinical Impact  
Mineral oil or other substances that may affect absorption of fat may influence the absorption of paricalcitol.
Intervention  
Recommend to take Paricalcitol capsules at least 1 hour before or 4 to  6  hours  after taking  mineral  oil  (or  at  as  great  an  interval  as possible) to avoid affecting absorption of paricalcitol.


Table name:
AED Coadministered AED Concentration Topiramate Concentration
Phenytoin NC or 25% increase a 48% decrease
Carbamazepine (CBZ) NC 40% decrease
CBZ epoxide b NC NE
Valproic acid 11% decrease 14% decrease
Phenobarbital NC NE
Primidone NC NE
Lamotrigine NC at TPM doses up to 400 mg/day 13% decrease


Table name:
Interacting Drug Interaction
Multivalent cationcontaining products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.12, 7.3)


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or 
Concomitant Drug
Clinical Comment 
↓= Decreased (induces lamotrigine gluronidation). ↑= Increased (inhibits lamotrigine glucuronidation). ?= Conflicting data.
Estrogen-containing oral 
contraceptive preparations 
containing 30 mcg ethinylestradiol 
and 150 mcg levonorgestrel
↓ lamotrigine



Decreased lamotrigine levels 
approximately 50%.


↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and 
CBZ epoxide
↓ lamotrigine
Addition of carbamazepine decreases lamotrigine 
concentration approximately 40%.
? CBZ epoxide May increase CBZ epoxide levels
Phenobarbital/Primidone ↓ lamotrigine Decreased lamotrigine 
concentration approximately 40%.
Phenytoin (PHT) ↓ lamotrigine Decreased lamotrigine 
concentration approximately 40%
Rifampin ↓ lamotrigine Decreased lamotrigine AUC 
approximately 40%
Valproate ↑ lamotrigine
Increased lamotrigine concentrations slightly 
more than 2-fold.
? valproate Decreased valproate concentrations an average of 
25% over a 3-week period then stabilized in healthy volunteers; 
no change in controlled clinical trials in epilepsy patients.


Table name:
Drug Description
Heparin Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients
Pyrazinamide Inhibits pyrazinamide-induced hyperuricemia
Uricosuric Agents Effect of probenecid, sulfinpyrazone and phenylbutazone inhibited


Table name:
Table 1: Clinically Significant Drug Interactions with Oxycodone HCl
Inhibitors of CYP3A4 and CYP2D6
Clinical Impact: The concomitant use of oxycodone HCl and CYP3A4 inhibitors can increase the plasma concentration of oxycodone, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of oxycodone HCl and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of oxycodone HCl is achieved [see Warnings and Precautions (5.4)]. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the oxycodone plasma concentration will decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to oxycodone.
Intervention: If concomitant use is necessary, consider dosage reduction of oxycodone HCl until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the oxycodone HCl dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir).
CYP3A4 Inducers
Clinical Impact: The concomitant use of oxycodone HCl and CYP3A4 inducers can decrease the plasma concentration of oxycodone [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to oxycodone [see Warnings and Precautions (5.12)]. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the oxycodone plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.
Intervention: If concomitant use is necessary, consider increasing the oxycodone HCl dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider oxycodone HCl dosage reduction and monitor for signs of respiratory depression.
Examples: Rifampin, carbamazepine, phenytoin
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.5)].
Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Adverse Reactions (6.2)].
Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue oxycodone HCl if serotonin syndrome is suspected.
Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)].
Intervention: The use of oxycodone HCl is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
Examples: phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist Opioid Analgesics
Clinical Impact: May reduce the analgesic effect of oxycodone HCl and/or may precipitate withdrawal symptoms.
Intervention: Avoid concomitant use
Examples: Butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact: Oxycodone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of oxycodone HCl and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention: Monitor patients for signs of dismissed diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact: The concomitant risk of anticholinergic drugs may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when oxycodone HCl is used concurrently with anticholinergic drugs.


Table name:
Factors Dosage Adjustments for Aripiprazole
Known CYP2D6 Poor Metabolizers Administer half of usual dose
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors Administer half of usual dose
Strong CYP2D6 and CYP3A4 inhibitors Administer a quarter of usual dose
Strong CYP3A4 inducers Double usual dose over 1 to 2 weeks


Table name:
Table 2. Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T4 and T3 serum transport - but FT4 concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors
(SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on
Concentration of Lamotrigine or Concomitant Drug
Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine Decreased lamotrigine concentrations approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? carbamazepine epoxide May increase carbamazepine epoxide levels.
 Lopinavir/ritonavir ↓ lamotrigine Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir ↓ lamotrigine Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine
Increased lamotrigine concentrations slightly more than 2-fold.
? valproate There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.


Table name:
Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s)
Recommendation
Comments
Tizanidine
Contraindicated
Concomitant administration of tizanidine and ciprofloxacin  is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2) ].
Theophylline
Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)
Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions (5.9) ].
Drugs Known to Prolong QT Interval
Avoid Use
 
Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see  Warnings and Precautions (5.11) and Use in Specific Populations (8.5) ].
Oral antidiabetic drugs
Use with caution Glucose-lowering effect potentiated
Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs [see Adverse Reactions (6.1) ].
Phenytoin
Use with caution Altered serum levels of phenytoin
(increased and decreased)
 
To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin with phenytoin.
Cyclosporine
Use with caution (transient elevations in serum creatinine)
Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs
Use with caution (Increase in anticoagulant effect)
The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate
Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels
Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole
Use with caution
Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin [see Warnings and Precautions (5.16) ].
Clozapine
Use with caution
Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs
Use with caution
Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil
Use with caution Two-fold increase in exposure
Monitor for sildenafil toxicity [see Clinical Pharmacology (12.3) ].
Duloxetine
Avoid Use
Five-fold increase in duloxetine exposure
If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives
Use with caution Reduced clearance resulting in elevated levels and prolongation
of serum half-life
Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx® (didanosine) chewable/ buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)
Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2.4) ].
Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid
Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)
Potentiation of ciprofloxacin toxicity may occur.


Table name:
Table 3: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 10 and 20 mg in BPH patients on stable alpha-blocker therapy with tamsulosin 0.4 or 0.8 mg daily (Study 2)
Vardenafil 10 mg
Placebo-subtracted
Vardenafil 20 mg
Placebo-subtracted
Standing SBP -4 (-6.8, -0.3) -4 (-6.8, -1.4)
Supine SBP -5 (-8.2, -0.8) -4 (-6.3, -1.8)


Table name:
 Interacting Drug  Interaction
 Drugs known to prolong QT interval (e.g., Class IA and Class III antiarrhythmic agents).  Quinine sulfate prolongs QT interval, ECG abnormalities including QT prolongation and Torsades de Pointes. Avoid concomitant use (5.3).
 Other antimalarials (e.g., halofantrine, mefloquine).  ECG abnormalities including QT prolongation. Avoid concomitant use (5.3, 7.2).
 CYP3A4 inducers or inhibitors  Alteration in plasma quinine concentration. Monitor for lack of efficacy or increased adverse events of quinine (7.1).
 CYP3A4 and CYP2D6 substrates  Quinine is an inhibitor of CYP3A4 and CYP2D6. Monitor for lack of efficacy or increased adverse events of the co-administered drug (7.2).
 Digoxin  Increased digoxin plasma concentration (5.8, 7.1).


Table name:
Table 8: Effect of Voriconazole on Pharmacokinetics of Other Drugs [see Clinical Pharmacology (12.3)]
Drug/Drug Class
(Mechanism of Interaction by Voriconazole)
Drug Plasma Exposure
(Cmax and AUCτ)
Recommendations for Drug Dosage Adjustment/Comments
SirolimusResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects
(CYP3A4 Inhibition)
Significantly Increased Contraindicated
Rifabutin
(CYP3A4 Inhibition)
Significantly Increased Contraindicated
Efavirenz (400 mg q24h)Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects
(CYP3A4 Inhibition)
Significantly Increased Contraindicated
Efavirenz (300 mg q24h)
(CYP3A4 Inhibition)
Slight Increase in AUCτ When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)(CYP3A4 Inhibition) No Significant Effect of Voriconazole on Ritonavir Cmax or AUCτ Contraindicated because of significant reduction of voriconazole Cmax and AUCτ
     
Low-dose Ritonavir (100 mg q12h) Slight Decrease in Ritonavir Cmax and AUCτ Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole Cmax and AUCτ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine
(CYP3A4 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids
(CYP450 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Contraindicated
Cyclosporine
(CYP3A4 Inhibition)
AUCτ Significantly Increased; No Significant Effect on Cmax When initiating therapy with VFEND in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When VFEND is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
MethadoneResults based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for 4 days voriconazole to subjects receiving a methadone maintenance dose (30–100 mg q24h) (CYP3A4 Inhibition) Increased Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl (CYP3A4 Inhibition)
Increased Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7)]
Alfentanil (CYP3A4 Inhibition) Significantly Increased Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with VFEND. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [see Drug Interactions (7)].
Oxycodone (CYP3A4 Inhibition) Significantly Increased Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7)].
NSAIDsNon-Steroidal Anti-Inflammatory Drug including. ibuprofen and diclofenac
(CYP2C9 Inhibition)
Increased Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed [see Drug Interactions (7)].
Tacrolimus
(CYP3A4 Inhibition)
Significantly Increased When initiating therapy with VFEND in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When VFEND is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin
(CYP2C9 Inhibition)
Significantly Increased Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition) Increased Monitoring for adverse events related to oral contraceptives is recommended during coadministration.
Warfarin
(CYP2C9 Inhibition)
Prothrombin Time Significantly Increased Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed.
Omeprazole
(CYP2C19/3A4 Inhibition)
Significantly Increased When initiating therapy with VFEND in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors
(CYP3A4 Inhibition)
In Vivo Studies Showed No Significant Effects on Indinavir Exposure No dosage adjustment for indinavir when coadministered with VFEND
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism
(Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors
(CYP3A4 Inhibition)
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs
(Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity related to NNRTI
Benzodiazepines
(CYP3A4 Inhibition)
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism
(Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.
HMG-CoA Reductase Inhibitors (Statins)
(CYP3A4 Inhibition)
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism
(Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers
(CYP3A4 Inhibition)
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism
(Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics
(CYP2C9 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids
(CYP3A4 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed.
Everolimus
(CYP3A4 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Concomitant administration of voriconazole and everolimus is not recommended.


Table name:
Table 9. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class:
Drug Name
Effect on Concentration of Lopinavir or Concomitant Drug Clinical Comments
HIV-1 Antiviral Agents
Non-nucleoside Reverse Transcriptase Inhibitors:
efavirenz*,
nevirapine*
↓ lopinavir KALETRA dose increase is recommended in all patients [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
Increasing the dose of KALETRA tablets to 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) twice daily co-administered with efavirenz resulted in similar lopinavir concentrations compared to KALETRA tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz.
Increasing the dose of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice daily co-administered with efavirenz resulted in significantly higher lopinavir plasma concentrations compared to KALETRA tablets 400/100 mg twice daily without efavirenz.
KALETRA should not be administered once daily in combination with efavirenz or nevirapine [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
Non-nucleoside Reverse Transcriptase Inhibitor:
delavirdine
↑ lopinavir Appropriate doses of the combination with respect to safety and efficacy have not been established.
Nucleoside Reverse Transcriptase Inhibitor:
didanosine
  KALETRA tablets can be administered simultaneously with didanosine without food.
For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food).
Nucleoside Reverse Transcriptase Inhibitor:
tenofovir
↑ tenofovir KALETRA increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir.
Nucleoside Reverse Transcriptase Inhibitor:
abacavir
zidovudine
↓ abacavir
↓ zidovudine
KALETRA induces glucuronidation; therefore, KALETRA has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown.
HIV-1 Protease Inhibitor:
amprenavir*
↑ amprenavir
↓ lopinavir
KALETRA should not be administered once daily in combination with amprenavir
[see Dosage and Administration (2.1)].
HIV-1 Protease Inhibitor:
fosamprenavir/ritonavir
↓ amprenavir
↓ lopinavir
An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor:
indinavir*
↑ indinavir Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily [see Clinical Pharmacology (12.3)]. KALETRA once daily has not been studied in combination with indinavir.
HIV-1 Protease Inhibitor:
nelfinavir*
↑ nelfinavir
↑ M8 metabolite of nelfinavir
↓ lopinavir
KALETRA should not be administered once daily in combination with nelfinavir
[see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].

HIV-1 Protease Inhibitor:
ritonavir*
↑ lopinavir Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor:
saquinavir*
↑ saquinavir The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily.
KALETRA once daily has not been studied in combination with saquinavir.
HIV-1 Protease Inhibitor:
tipranavir
↓ lopinavir AUC and Cmin KALETRA should not be administered with tipranavir (500 mg twice daily) co-administered with ritonavir (200 mg twice daily).
HIV CCR5 – Antagonist:
maraviroc
↑ maraviroc Concurrent administration of maraviroc with KALETRA will increase plasma levels of maraviroc. When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for Selzentry® (maraviroc).
Other Agents
Antiarrhythmics:
amiodarone,
bepridil,
lidocaine (systemic),
quinidine
↑ antiarrhythmics Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA.
Anticancer Agents:
vincristine,
vinblastine,
dasatinib,
nilotinib
↑ anticancer agents Concentrations of these drugs may be increased when co-administered with KALETRA resulting in the potential for increased adverse events usually associated with these anticancer agents.
For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when KALETRA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor.
A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as KALETRA. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions.
Anticoagulant:
warfarin
  Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants:
carbamazepine,
phenobarbital,
phenytoin
↓ lopinavir
↓ phenytoin
KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution.
KALETRA should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin.

In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA.
Antidepressant:
bupropion
↓ bupropion
↓ active metabolite,
hydroxybupropion
Concurrent administration of bupropion with KALETRA may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion.
Antidepressant:
trazodone
↑ trazodone Concomitant use of trazodone and KALETRA may increase concentrations of trazodone. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered.
Anti-infective:
clarithromycin
↑ clarithromycin For patients with renal impairment, the following dosage adjustments should be considered:
  • For patients with CLCR 30 to 60 mL/min the dose
    of clarithromycin should be reduced by 50%.
  • For patients with CLCR < 30 mL/min the dose
    of clarithromycin should be decreased by 75%.

No dose adjustment for patients with normal renal function is necessary.
Antifungals:
ketoconazole*,
itraconazole,
voriconazole
↑ ketoconazole
↑ itraconazole
↓ voriconazole
High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended.
Co-administration of voriconazole with KALETRA has not been studied. However, a study has been shown that administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%; therefore, co-administration of KALETRA and voriconazole may result in decreased voriconazole concentrations and the potential for decreased voriconazole effectiveness and should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Otherwise, alternative antifungal therapies should be considered in these patients.
Anti-gout:
colchicine
↑ colchicine Patients with renal or hepatic impairment should not be given colchicine with KALETRA.

Treatment of gout flares-co-administration of colchicine in patients on KALETRA:

0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days.

Prophylaxis of gout flares-co-administration of colchicine in patients on KALETRA:

If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.

If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.

Treatment of familial Mediterranean fever (FMF)-co-administration of colchicine in patients on KALETRA:

Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Antimycobacterial:
rifabutin*
↑ rifabutin and rifabutin metabolite Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary.
Antimycobacterial:
rifampin
↓ lopinavir May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents. A study evaluated combination of rifampin 600 mg once daily, with KALETRA 800/200 mg twice daily or KALETRA 400/100 mg + ritonavir 300 mg twice daily. Pharmacokinetic and safety results from this study do not allow for a dose recommendation. Nine subjects (28%) experienced a ≥ grade 2 increase in ALT/AST, of which seven (21%) prematurely discontinued study per protocol. Based on the study design, it is not possible to determine whether the frequency or magnitude of the ALT/AST elevations observed is higher than what would be seen with rifampin alone [see Clinical Pharmacology (12.3) for magnitude of interaction].
Antiparasitic:
atovaquone
↓ atovaquone Clinical significance is unknown; however, increase in atovaquone doses may be needed.
Benzodiazepines: parenterally administered midazolam ↑ midazolam Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, KALETRA should not be given with orally administered midazolam [see Contraindications (4)]. If KALETRA is co-administered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.
Calcium Channel Blockers:
dihydropyridine,
felodipine,
nifedipine,
nicardipine
↑ dihydropyridine calcium channel blockers Caution is warranted and clinical monitoring of patients is recommended.
Contraceptive:
ethinyl estradiol*
↓ ethinyl estradiol Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended.
Corticosteroid:
dexamethasone

↓ lopinavir Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly.


disulfiram/metronidazole   KALETRA oral solution contains alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).
Endothelin Receptor Antagonists:
bosentan
↑ bosentan Co-administration of bosentan in patients on KALETRA:

In patients who have been receiving KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

Co-administration of KALETRA in patients on bosentan:

Discontinue use of bosentan at least 36 hours prior to initiation of KALETRA.

After at least 10 days following the initiation of KALETRA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
HMG-CoA Reductase Inhibitors:
atorvastatin
rosuvastatin
↑ atorvastatin
↑ rosuvastatin
Use atorvastatin with caution and at the lowest necessary dose. Titrate rosuvastatin dose carefully and use the lowest necessary dose; do not exceed rosuvastatin 10 mg/day. See Drugs with No Observed or Predicted Interactions with KALETRA ( 7.4 ) and Clinical Pharmacology (12.3) for drug interaction data with other HMG-CoA reductase inhibitors.
Immunosuppressants:
cyclosporine,
tacrolimus,
rapamycin
↑ immunosuppressants Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA.
Inhaled Steroid:
fluticasone
↑ fluticasone Concomitant use of fluticasone propionate and KALETRA may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during post-marketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Co-administration of fluticasone propionate and KALETRA is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effect.
Long-acting beta-adrenoceptor Agonist:
salmeterol
↑ salmeterol Concurrent administration of salmeterol and KALETRA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Narcotic Analgesic:
methadone*
fentanyl
↓ methadone
↑ fentanyl
Dosage of methadone may need to be increased when co-administered with KALETRA.
Concentrations of fentanyl are expected to increase. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with KALETRA.
PDE5 inhibitors:
sildenafil,
tadalafil,
vardenafil
↑ sildenafil
↑ tadalafil
↑ vardenafil
Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs is expected to substantially increase their concentrations and may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection.

Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH):

Sildenafil (Revatio®) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with KALETRA [see Contraindications (4)].

The following dose adjustments are recommended for use of tadalafil (Adcirca®) with KALETRA:

Co-administration of ADCIRCA in patients on KALETRA:

In patients receiving KALETRA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Co-administration of KALETRA in patients on ADCIRCA:

Avoid use of ADCIRCA during the initiation of KALETRA. Stop ADCIRCA at least 24 hours prior to starting KALETRA. After at least one week following the initiation of KALETRA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Use of PDE5 inhibitors for erectile dysfunction:

It is recommended not to exceed the following doses:
  • Sildenafil: 25 mg every 48 hours
  • Tadalafil: 10 mg every 72 hours
  • Vardenafil: 2.5 mg every 72 hours

Use with increased monitoring for adverse events.
*   see Clinical Pharmacology (12.3) for magnitude of interaction.


Table name:
Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme
Inhibitors
Inducers
CYP2C9 
amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast
aprepitant, bosentan, carbamazepine, phenobarbital, rifampin 
CYP1A2 
acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton
montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking 
CYP3A4 
alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton
armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide 


Table name:
Drug/Drug Class
(Mechanism of Interaction by the Drug)

Voriconazole Plasma Exposure
(Cmax and AUCτ after 200 mg q12h)

Recommendations for Voriconazole Dosage Adjustment/Comments
Rifampin* and Rifabutin*
(CYP450 Induction)
Significantly Reduced
Contraindicated
Efavirenz (400 mg q24h)
(CYP450 Induction)
 
Efavirenz (300 mg q24h)
(CYP450 Induction)
Significantly Reduced
 
 
Slight Decrease in AUCτ
Contraindicated
 
 
When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High dose Ritonavir (400 mg q12h)
(CYP450 Induction)
Low dose Ritonavir (100 mg q12h)
(CYP450 Induction)
 
Significantly Reduced
 
 
Reduced
 
Contraindicated
 
 
Coadministration of voriconazole and low dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Carbamazepine
(CYP450 Induction)
Not Studied In Vivo or In Vitro, but Likely
to Result in Significant Reduction
Contraindicated
Long -acting Barbiturates
(CYP450 Induction)
Not Studied In Vivo or In Vitro, but Likely
to Result in Significant Reduction
Contraindicated
Phenytoin*
(CYP450 Induction)
Significantly Reduced
Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg)
St. John's Wort
(CYP450 inducer; P-gp inducer)
Significantly Reduced
Contraindicated
Oral Contraceptives
containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)
Increased
Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole (CYP2C9, CYP2C19 and CYP3A4 Inhibition)
Significantly Increased
Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole.
Other HIV Protease Inhibitors
(CYP3A4 Inhibition)
In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure
 
In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)
No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir
 
Frequent monitoring for adverse events and toxicity related  to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIs
(CYP3A4 Inhibition or CYP450 Induction)
In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure)
 
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs
(Decreased Plasma Exposure)
 Frequent monitoring for adverse events and toxicity related to voriconazole
 
 
Careful assessment of voriconazole effectiveness


Table name:
Table 2: Clinically Significant Drug Interactions with Alfentanil HCl Injection
Inhibitors of CYP3A4 and CYP2D6
Clinical Impact: The concomitant use of Alfentanil HCl Injection and CYP3A4 inhibitors can increase the plasma concentration of alfentanil, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of Alfentanil HCl Injection and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of Alfentanil HCl Injection is achieved [see Warnings and Precautions (5.4)].
After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the alfentanil plasma concentration will decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to alfentanil.
Intervention: If concomitant use is necessary, consider dosage reduction of Alfentanil HCl Injection until stable drug effects are achieved [see Dosage and Administration (2.2)]. Monitor patients for respiratory depression and sedation at frequent intervals.
If a CYP3A4 inhibitor is discontinued, consider increasing the Alfentanil HCl Injection dosage until stable drug effects are achieved [see Dosage and Administration (2.2)]. Monitor for signs of opioid withdrawal.
Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)
CYP3A4 Inducers
Clinical Impact: The concomitant use of Alfentanil HCl Injection and CYP3A4 inducers can decrease the plasma concentration of alfentanil [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to alfentanil [see Warnings and Precautions (5.13)].
After stopping a CYP3A4 inducer, as the effects of the inducer decline, the alfentanil plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.
Intervention: If concomitant use is necessary, consider increasing the Alfentanil HCl Injection dosage until stable drug effects are achieved [see Dosage and Administration (2.2)]. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider Alfentanil HCl Injection dosage reduction and monitor for signs of respiratory depression.
Examples: Rifampin, carbamazepine, phenytoin
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact: Diazepam administered immediately prior to or in conjunction with high doses of Alfentanil HCl Injection may produce vasodilation and hypotension, and may result in delayed recovery. Both the magnitude and duration of central nervous system and cardiovascular effects may be enhanced when Alfentanil HCl Injection is administered in combination with other CNS depressants such as barbiturates, tranquilizers, opioids, or inhalation general anesthetics. Postoperative respiratory depression may be enhanced or prolonged by these agents.
Intervention: Monitor patients receiving Alfentanil HCl Injection and benzodiazepines or other CNS depressants for hypotension patients and prolonged respiratory depression and sedation. In such cases of combined treatment, the dose of one or both agents should be reduced. Limited clinical experience indicates that requirements for volatile inhalation anesthetics are reduced by 30 to 50% for the first sixty (60) minutes following alfentanil induction. [see Warnings and Precautions (5.2)].
Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Warnings and Precautions (5.7)].
Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Alfentanil HCl Injection if serotonin syndrome is suspected.
Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors
Clinical Impact: Severe and unpredictable potentiation of monoamine oxidase (MAO) inhibitors has been reported rarely with alfentanil. MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)]
Intervention: When Alfentanil HCl Injection is administered to patients who have received MAO inhibitors within 14 days, monitor patients for hypertension and ensure ready availability of vasodilators and beta-blockers for the treatment of hypertension as needed.
Examples: phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact: May reduce the analgesic effect of Alfentanil HCl Injection and/or precipitate withdrawal symptoms.
Intervention: Avoid concomitant use.
Examples: butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact: Alfentanil may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Alfentanil HCl Injection and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when Alfentanil HCl Injection is used concomitantly with anticholinergic drugs.
Cimetidine
Clinical Impact: Cimetidine reduces the clearance of alfentanil, extending the duration of action.
Intervention: Use smaller alfentanil doses for prolonged administration and monitor closely for respiratory depression and other effects of alfentanil.
Nitrous oxide
Clinical Impact: Nitrous oxide has been reported to produce cardiovascular depression when given with higher doses of Alfentanil HCl Injection.
Intervention: Monitor patients for signs of cardiovascular depression that may be greater than otherwise expected.


Table name:
edema hereditary coumarin resistance hyperlipemia

hypothyroidism nephrotic syndrome


Table name:
Table 7. Effect of Voriconazole on Pharmacokinetics of Other Drugs [see Clinical Pharmacology (12.3)]
 Drug/Drug Class
(Mechanism of Interaction by
Voriconazole)
 Drug Plasma Exposure
(C max and AUC τ )
  Recommendations for Drug Dosage
Adjustment/Comments
 Sirolimus*
(CYP3A4 Inhibition)
 Significantly Increased  Contraindicated
 Rifabutin*
(CYP3A4 Inhibition)
 Significantly Increased  Contraindicated
 Efavirenz (400 mg q24h)**
(CYP3A4 Inhibition) 
 Significantly Increased  Contraindicated
 Efavirenz (300 mg q24h)**
(CYP3A4 Inhibition)
Slight Increase in AUCτ   When voriconazole is coadministered
with efavirenz, voriconazole oral
maintenance dose should be increased
to 400 mg q12h and efavirenz should
be decreased to 300 mg q24h 
 High-dose Ritonavir (400 mg
q12h)**(CYP3A4 Inhibition)
 No Significant Effect of Voriconazole
on Ritonavir Cmax or AUCτ
 Contraindicated because of significant reduction of voriconazole
Cmax and AUCτ
 Low-dose Ritonavir (100 mg
q12h)**
 Slight Decrease in Ritonavir Cmax
and AUCτ
 Coadministration of voriconazole and
low-dose ritonavir (100 mg q12h)
should be avoided (due to the
reduction in voriconazole Cmax and
AUCτ) unless an assessment of the
benefit/risk to the patient justifies the
use of voriconazole
 Terfenadine, Astemizole, Cisapride,
Pimozide, Quinidine
(CYP3A4 Inhibition)
 Not Studied In Vivo or In Vitro, but
Drug Plasma Exposure Likely to be
Increased
 Contraindicated because of potential
for QT prolongation and rare
occurrence of torsade de pointes
 Ergot Alkaloids
(CYP450 Inhibition)
 Not Studied In Vivo or In Vitro, but
Drug Plasma Exposure Likely to be
Increased
 Contraindicated
 Cyclosporine*
(CYP3A4 Inhibition)
 AUCτ Significantly Increased; No
Significant Effect on Cmax
 When initiating therapy with voriconazole in patients already
receiving cyclosporine, reduce the
cyclosporine dose to one-half of the
starting dose and follow with frequent
monitoring of cyclosporine blood
levels. Increased cyclosporine levels
have been associated with
nephrotoxicity. When
voriconazole is discontinued,
cyclosporine concentrations must be
frequently monitored and the dose
increased as necessary.
 Methadone***
(CYP3A4 Inhibition)
 Increased  Increased plasma concentrations of
methadone have been associated with
toxicity including QT prolongation.
Frequent monitoring for adverse events and toxicity related to
methadone is recommended during
coadministration. Dose reduction of
methadone may be needed
 Fentanyl (CYP3A4 Inhibition)  Increased  Reduction in the dose of fentanyl and
other long-acting opiates metabolized
by CYP3A4 should be considered
when coadministered with voriconazole. Extended and frequent
monitoring for opiate-associated
adverse events may be necessary [see Drug Interactions (7) ]
 Alfentanil (CYP3A4 Inhibition)  Significantly Increased  Reduction in the dose of alfentanil and
other opiates metabolized by CYP3A4
(e.g., sufentanil) should be considered
when coadministered with voriconazole. A longer period for
monitoring respiratory and other
opiate-associated adverse events may
be necessary [see Drug Interactions (7) ].
 Oxycodone (CYP3A4 Inhibition)  Significantly Increased  Reduction in the dose of oxycodone
and other long-acting opiates
metabolized by CYP3A4 should be
considered when coadministered with
voriconazole. Extended and
frequent monitoring for opiate-
associated adverse events may be
necessary [see Drug Interactions (7) ].
 NSAIDs**** including. ibuprofen
and diclofenac
(CYP2C9 Inhibition)
 Increased  Frequent monitoring for adverse
events and toxicity related to NSAIDs.
Dose reduction of NSAIDs may be
needed [see Drug Interactions (7) ].
 Tacrolimus*
(CYP3A4 Inhibition)
 Significantly Increased  When initiating therapy with
voriconazole in patients
already receiving tacrolimus, reduce
the tacrolimus dose to one-third of the
starting dose and follow with frequent
monitoring of tacrolimus blood levels.
Increased tacrolimus levels have been
associated with nephrotoxicity. When
voriconazole is discontinued,
tacrolimus concentrations must be
frequently monitored and the dose
increased as necessary.
 Phenytoin*
(CYP2C9 Inhibition)
 Significantly Increased  Frequent monitoring of phenytoin
plasma concentrations and frequent
monitoring of adverse effects related
to phenytoin.
 Oral Contraceptives containing
ethinyl estradiol and norethindrone
(CYP3A4 Inhibition)**
 Increased  Monitoring for adverse events related
to oral contraceptives is recommended
during coadministration.
 Warfarin*
(CYP2C9 Inhibition)
 Prothrombin Time Significantly
Increased
 Monitor PT or other suitable anti-
coagulation tests. Adjustment of
warfarin dosage may be needed.
 Omeprazole*
(CYP2C19/3A4 Inhibition)
 Significantly Increased  When initiating therapy with
voriconazole in patients
already receiving omeprazole doses of
40 mg or greater, reduce the
omeprazole dose by one-
half. The metabolism of other proton
pump inhibitors that are CYP2C19
substrates may also be inhibited by
voriconazole and may result in
increased plasma concentrations of
other proton pump inhibitors.
 Other HIV Protease Inhibitors
(CYP3A4 Inhibition)
 In Vivo Studies Showed No
Significant Effects on Indinavir
Exposure
 No dosage adjustment for indinavir
when coadministered with
voriconazole
   In Vitro Studies Demonstrated
Potential for Voriconazole to Inhibit
Metabolism (Increased Plasma
Exposure)
 Frequent monitoring for adverse
events and toxicity related to other
HIV protease inhibitors
 Other NNRTIs*****
(CYP3A4 Inhibition)
 A Voriconazole-Efavirenz Drug
Interaction Study Demonstrated the
Potential for Voriconazole to Inhibit
Metabolism of Other NNRTIs
(Increased Plasma Exposure)
 Frequent monitoring for adverse
events and toxicity related to NNRTI
 Benzodiazepines
(CYP3A4 Inhibition)
 In Vitro Studies Demonstrated
Potential for Voriconazole to Inhibit
Metabolism (Increased Plasma
Exposure)
 Frequent monitoring for adverse
events and toxicity (i.e., prolonged
sedation) related to benzodiazepines
metabolized by CYP3A4 (e.g.,
midazolam, triazolam, alprazolam).
Adjustment of benzodiazepine dosage
may be needed.
 HMG-CoA Reductase Inhibitors
(Statins)
(CYP3A4 Inhibition)
 In Vitro Studies Demonstrated
Potential for Voriconazole to Inhibit
Metabolism (Increased Plasma
Exposure)
 Frequent monitoring for adverse
events and toxicity related to statins.
Increased statin concentrations in
plasma have been associated with
rhabdomyolysis. Adjustment of the
statin dosage may be needed.
 Dihydropyridine Calcium Channel
Blockers
(CYP3A4 Inhibition)
 In Vitro Studies Demonstrated
Potential for Voriconazole to Inhibit
Metabolism (Increased Plasma
Exposure)
 Frequent monitoring for adverse
events and toxicity related to calcium
channel blockers. Adjustment of
calcium channel blocker dosage may
be needed.
 Sulfonylurea Oral Hypoglycemics
(CYP2C9 Inhibition)
 Not Studied In Vivo or In Vitro, but
Drug Plasma Exposure Likely to be
Increased
 Frequent monitoring of blood glucose
and for signs and symptoms of
hypoglycemia. Adjustment of oral
hypoglycemic drug dosage may be
needed.
 Vinca Alkaloids
(CYP3A4 Inhibition)
 Not Studied In Vivo or In Vitro, but
Drug Plasma Exposure Likely to be
Increased
 Frequent monitoring for adverse
events and toxicity (i.e., neurotoxicity)
related to vinca alkaloids. Adjustment
of vinca alkaloid dosage may be
needed.
 Everolimus Not Studied In Vivo or In Vitro, but
Drug Plasma Exposure Likely to be
Increased 
Concomitant administration of voriconazole and everolimus is not recommended. 


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium ( 2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( 7.2)
Antidiabetic agents Carefully monitor blood glucose ( 5.12, 7.3)


Table name:
Drugs that Affect Renal Function A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDS], COX-2 inhibitors may impair the excretion of digoxin.
Antiarrthymics Dofetilide Concomitant administration with digoxin was associated with a higher rate of torsades de pointes
Sotalol Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
Dronedarone Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone Analog Teriparatide Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement Thyroid Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics Epinephrine
Norepinephrine     
Dopamine
Can increase the risk of cardiac arrhythmias
Neuromuscular Blocking Agents      Succinylcholine May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.
Supplements Calcium If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine Decreased lamotrigine levels approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? CBZ epoxide May increase CBZ epoxide levels.
Phenobarbital/Primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT) ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine Increased lamotrigine concentrations slightly more than 2 fold.
? valproate Decreased valproate concentrations an average of 25% over a 3 week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.During concomitant use of celecoxib capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of celecoxib capsules and ACE-inhibitors or ARBs in patients who are elderly, volume- depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6) ]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Drugs That Interfere with Hemostasis
  Clinical Impact: Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of celecoxib capsules with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11) ].
Aspirin
   Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2) ]. In two studies in healthy volunteers, and in patients with osteoarthritis and established heart disease respectively, celecoxib (200-400 mg daily) has demonstrated a lack of interference with the cardioprotective antiplatelet effect of aspirin (100-325 mg).
Intervention: Concomitant use of celecoxib capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11) ]. Celecoxib capsules are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
  Clinical Impact:
1. 2.
   Intervention:
1. 2. 3.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of celecoxib capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6) ].
Digoxin
Clinical Impact: The concomitant use of celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of celecoxib capsules and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of celecoxib capsules and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Celecoxib capsules have no effect on methotrexate pharmacokinetics.
Intervention: During concomitant use of celecoxib capsules and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of celecoxib capsules and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of celecoxib capsules and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2) ].
Intervention: The concomitant use of celecoxib with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of celecoxib capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of celecoxib capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.
NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.
In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
CYP2C9 Inhibitors or inducers
Clinical Impact: Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Co‑-administration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of celecoxib.
Intervention Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers [see Clinical Pharmacology (12.3) ].
CYP2D6 substrates
Clinical Impact: In vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6 (e.g. atomoxetine), and celecoxib may enhance the exposure and toxicity of these drugs.
Intervention Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2D6 substrates [see Clinical Pharmacology (12.3) ].
Corticosteroids
Clinical Impact: Concomitant use of corticosteroids with celecoxib capsules may increase the risk of GI ulceration or bleeding.
Intervention Monitor patients with concomitant use of celecoxib capsules with corticosteroids for signs of bleeding [see Warnings and Precautions (5.2)].


Table name:
  a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
b = Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated
AED Co-administered 
AED Concentration
Topiramate Concentration
Phenytoin 
NC or 25% increasea
48% decrease
Carbamazepine (CBZ)
NC 
40% decrease
CBZ epoxideb
NC
NE
Valproic acid 
11% decrease
14% decrease
Phenobarbital
NC
NE
Primidone 
NC
NE
Lamotrigine 
NC at TPM doses up to 400 mg/day
13% decrease


Table name:
AED Coadministered AED Concentration Topiramate Concentration
Phenytoin NC or 25% increasea 48% decrease
Carbamazepine (CBZ) NC 40% decrease
CBZ epoxideb NC NE
Valproic acid 11% decrease 14% decrease
Phenobarbital NC NE
Primidone NC NE
Lamotrigine NC at TPM doses up to 400 mg/day 13% decrease


Table name:
Table 3: Drugs that Can Increase the Risk of Bleeding
 Drug Class  Specific Drugs
 Anticoagulants  argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
 Antiplatelet Agents  aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
 Nonsteroidal Anti-Inflammatory Agents  celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
 Serotonin Reuptake Inhibitors  citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitors (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Interacting Drug Interaction
Theophylline Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin Monitor phenytoin level (7)
Methotrexate Monitor for methotrexate toxicity (7)
Cyclosporine May increase serum creatinine. Monitor serum creatinine (7)
Multivalent cation-containing products including antacids, metal cations or didanosine Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin (7)


Table name:
Table 6. Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology (12.3)]
Drug/Drug Class (Mechanism of Interaction by the Drug) Voriconazole Plasma Exposure (Cmax and AUC τ after 200 mg q12h) Recommendations for Voriconazole Dosage Adjustment/Comments
RifampinResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg q12h voriconazole to healthy subjects and Rifabutin  (CYP450 Induction) Significantly Reduced Contraindicated
Efavirenz (400 mg q24h)Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects (CYP450 Induction)
 
Efavirenz (300 mg q24h)
(CYP450 Induction)
Significantly Reduced
 
Slight Decrease in AUCτ
Contraindicated
 
When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High dose Ritonavir (400 mg q12h) (CYP450 Induction) Significantly Reduced Contraindicated
Low dose Ritonavir (100 mg q12h) (CYP450 Induction) Reduced Coadministration of voriconazole and low dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Carbamazepine (CYP450 Induction) Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction Contraindicated
Long-acting Barbiturates (CYP450 Induction) Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction Contraindicated
Phenytoin (CYP450 Induction) Significantly Reduced Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg)
St. John’s Wort (CYP450 inducer; P-gp inducer) Significantly Reduced Contraindicated
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition) Increased Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole
(CYP2C9, CYP2C19 and CYP3A4 Inhibition)
Significantly Increased Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole.
Other HIV Protease Inhibitors (CYP3A4 Inhibition) In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir
In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors (CYP3A4 Inhibition or CYP450 Induction) In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to voriconazole
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure) Careful assessment of voriconazole effectiveness


Table name:
DRUG DESCRIPTION OF INTERACTION
Sulfonylureas Hypoglycemia potentiated.
Methotrexate Decreases tubular reabsorption; clinical toxicity from methotrexate can result.
Oral Anticoagulants Increased bleeding.


Table name:
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Do not exceed 40 mg atorvastatin daily


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including : antacids, sucralfate, multivitamins Decreased moxifloxacin hydrochloride absorption. Take moxifloxacin hydrochloride tablets at least 4 hours before or 8 hours after these products. (2.2, 7.1, 12.3
Warfarin Anticoagulant effect enhanced. Monitor prothrombin time/INR, and bleeding. (6, 7.2, 12.3)
Class IA and Class III antiarrhythmics: Proarrhythmic effect may be enhanced. Avoid concomitant use. (5.6, 7.5)
Antidiabetic agents Carefully monitor blood glucose. (5.11, 7.3)


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
 Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration  Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
 Drugs that may alter T 4 and T 3 metabolism
 Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
TABLE 2. Mean (± S.D.) Pharmacokinetic Parameters for Estradiol, Estrone, and Equilin Following Coadministration of Conjugated Estrogens 0.625 mg and Progesterone Capsules 200 mg for 12 Days to Postmenopausal Women
a Total estrogens is the sum of conjugated and unconjugated estrogen.
  Conjugated Estrogens Conjugated Estrogens plus Progesterone Capsules
Drug C max
(ng/mL)
T max
(hr)
AUC (0-24h)
(ng × h/mL)
C max
(ng/mL)
T max
(hr)
AUC (0-24h)
(ng × h/mL)
Estradiol 0.037
± 0.048
12.7
± 9.1
0.676
± 0.737
0.030
± 0.032
17.32
± 1.21
0.561
± 0.572
Estrone
Total a
3.68
± 1.55
10.6
± 6.8
61.3
± 26.36
4.93
± 2.07
7.5
± 3.8
85.9
± 41.2
Equilin
Total a
2.27
± 0.95
6.0
± 4.0
28.8
± 13.0
3.22
± 1.13
5.3
± 2.6
38.1
± 20.2


Table name:
Table 7. Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology (12.3)]
Drug/Drug Class
(Mechanism of Interaction by the Drug)
Voriconazole Plasma Exposure
(Cmax and AUCτ after 200 mg q12h)
Recommendations for Voriconazole Dosage Adjustment/Comments
Rifampin* and Rifabutin*
(CYP450 Induction)
Significantly Reduced Contraindicated
Efavirenz (400 mg q 24h)** (CYP450 Induction) Efavirenz (300 mg q 24h) ** (CYP450 Induction) Significantly Reduced Slight decrease in AUCt Contraindicated When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)** (CYP450 Induction) Significantly Reduced Contraindicated
Low-dose Ritonavir (100 mg q12h)** (CYP450 Induction) Reduced Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Carbamazepine
(CYP450 Induction)
Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction Contraindicated
Long Acting Barbiturates
(CYP450 Induction)
Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction Contraindicated
Phenytoin*
(CYP450 Induction)
Significantly Reduced Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg)
St. John’s Wort
(CYP450 inducer; P-gp inducer)
Significantly Reduced Contraindicated
Oral Contraceptives**
containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)
Increased Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole** (CYP2C9, CYP2C19 and CYP3A4 Inhibition) Significantly Increased Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole.
Other HIV Protease Inhibitors
(CYP3A4 Inhibition)
In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure
In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)
No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIs*** (CYP3A4 Inhibition or CYP450 Induction) In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to voriconazole
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure) Careful assessment of voriconazole effectiveness


Table name:
Concomitant Drug Name or Drug Class
Clinical Rationale
Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) 
The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].
With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)
The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].
With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Antihypertensive Drugs
Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.
Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.8)]. 
Benzodiazepines (e.g., lorazepam)
The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.8)]
Monitor sedation and blood pressure. Adjust dose accordingly.


Table name:
Table 18. Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
*Change relative to reference
Coadministered Drug
 
Dosing Schedule
Effect on Active Moiety
(Risperidone + 9- Hydroxy-
Risperidone (Ratio*)
Risperidone Dose
Recommendation
Coadministered Drug
Risperidone
AUC
Cmax
Enzyme (CYP2D6) inhibitors
 
 
 
 
Fluoxetine
20 mg/day
2 or 3 mg twice daily
1.4
1.5

Re-evaluate dosing.
Do not exceed 8 mg/day
Paroxetine
10 mg/day
4 mg/day
1.3
-

Re-evaluate dosing.
Do not exceed 8 mg/day
20 mg/day
4 mg/day
1.6
-
40 mg/day
4 mg/day
1.8
-
Enzyme (CYP3A/ PgP inducers) Inducers
 
 
 
 
 
Carbamazepine
573 ± 168 mg/day
 
3 mg twice daily
 
0.51
 
0.55
 

Titrate dose upwards.
Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) inhibitors
 
 
 
 
 
Ranitidine
150 mg twice daily
1 mg single dose
1.2
1.4
Dose adjustment not needed
Cimetidine
400 mg twice daily
1 mg single dose
1.1
1.3
Dose adjustment not needed
Erythromycin
500 mg four times daily
1 mg single dose
1.1
0.94
Dose adjustment not needed
Other Drugs
 
 
 
 
 
Amitriptyline
50 mg twice daily
3 mg twice daily
1.2
1.1
Dose adjustment not Needed


Table name:
Table 2: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 5 mg in BPH patients on stable alpha-blocker therapy (Study 1)
Alpha-Blocker Simultaneous dosing of Vardenafil 5 mg
and Alpha-Blocker,
Placebo-Subtracted
Dosing of Vardenafil 5 mg
and Alpha-Blocker
Separated by 6 Hours,
Placebo-Subtracted
Terazosin
5 or 10 mg daily
Standing SBP -3 (-6.7, 0.1) -4 (-7.4, -0.5)
Supine SBP -4 (-6.7, -0.5) -4 (-7.1, -0.7)
Tamsulosin
0.4 mg daily
Standing SBP
Supine SBP
-6 (-9.9, -2.1)
-4 (-7.0, -0.8)
-4 (-8.3, -0.5)
-5 (-7.9, -1.7)


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir ) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name: Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology (12.3)]. Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see Clinical Pharmacology (12.3)]. There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole.
Antiretrovirals
Clinical Impact: The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known.
Intervention: Rilpivirine-containing products: Concomitant use with omeprazole is contraindicated [see Contraindications (4)]. Atazanavir: Avoid concomitant use with omeprazole. See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with omeprazole. See prescribing information for nelfinavir. Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities. Other antiretrovirals: See prescribing information for specific antiretroviral drugs.
Warfarin
Clinical Impact: Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
Intervention: Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range.
Methotrexate
Clinical Impact: Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions (5.11)].
Intervention: A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate.
CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam)
Clopidogrel
Clinical Impact: Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology (12.3)]. There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel.
Intervention: Avoid concomitant use with omeprazole. Consider use of alternative
anti-platelet therapy [see Warnings and Precautions (5.6)].
Citalopram
Clinical Impact: Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology (12.3)].
Intervention: Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.
Cilostazol
Clinical Impact: Increased exposure of one of the active metabolites of cilostazol
(3,4-dihydro-cilostazol) [see Clinical Pharmacology (12.3)].
Intervention: Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.
Phenytoin
Clinical Impact: Potential for increased exposure of phenytoin.
Intervention: Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin.
Diazepam
Clinical Impact: Increased exposure of diazepam [see Clinical Pharmacology (12.3)].
Intervention: Monitor patients for increased sedation and reduce the dose of diazepam as needed.
Digoxin
Clinical Impact: Potential for increased exposure of digoxin [see Clinical Pharmacology (12.3)].
Intervention: Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)
Clinical Impact: Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
Intervention: Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF [see Clinical Pharmacology (12.3)]. See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact: Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions.
Intervention: See Contraindications, Warnings and Precautions in prescribing information for clarithromycin. See Drug Interactions in prescribing information for amoxicillin.
Tacrolimus
Clinical Impact: Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.
Intervention: Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact: Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions (5.10), Clinical Pharmacology (12.2)].
Intervention: Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
Interaction with Secretin Stimulation Test
Clinical Impact: Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention: Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology (12.2)].
False Positive Urine Tests for THC
Clinical Impact: There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.
Intervention: An alternative confirmatory method should be considered to verify positive results.
Other
Clinical Impact: There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram).
Intervention: Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole.


Table name:
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Do not exceed 40 mg atorvastatin daily


Table name:
  a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
b = Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated
AED Co-administered 
AED Concentration
Topiramate Concentration
Phenytoin 
NC or 25% increasea
48% decrease
Carbamazepine (CBZ)
NC 
40% decrease
CBZ epoxideb
NC
NE
Valproic acid 
11% decrease
14% decrease
Phenobarbital
NC
NE
Primidone 
NC
NE
Lamotrigine 
NC at TPM doses up to 400 mg/day
13% decrease


Table name:
Table 6. Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology (12.3)]
  Drug/Drug Class
(Mechanism of Interaction by the Drug)
  Voriconazole Plasma Exposure
(Cmax and AUCτ after 200 mg q12h)
  Recommendations for Voriconazole Dosage Adjustment/Comments
 Rifampin* and Rifabutin*
(CYP450 Induction)
 Significantly Reduced   Contraindicated
 Efavirenz (400 mg q 24h)**
(CYP450 Induction)
Efavirenz (300 mg q 24h) ** (CYP450 Induction)
 Significantly Reduced Slight decrease in AUCt   Contraindicated When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
 High-dose Ritonavir (400 mg q12h)** (CYP450 Induction)  Significantly Reduced   Contraindicated
 Low-dose Ritonavir (100 mg q12h)** (CYP450 Induction)  Reduced  Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
 Carbamazepine
(CYP450 Induction)
 Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction   Contraindicated
 Long Acting Barbiturates
(CYP450 Induction)
 Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction   Contraindicated
 Phenytoin*
(CYP450 Induction)
 Significantly Reduced  Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg)
 St. John’s Wort
(CYP450 inducer; P-gp inducer)
 Significantly Reduced   Contraindicated
 Oral Contraceptives**
containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)
 Increased  Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
 Fluconazole** (CYP2C9, CYP2C19 and CYP3A4 Inhibition)  Significantly Increased  Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole.
 Other HIV Protease Inhibitors
(CYP3A4 Inhibition)
  In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure
In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)
 No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
 Other NNRTIs*** (CYP3A4 Inhibition or CYP450 Induction)   In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure)  Frequent monitoring for adverse events and toxicity related to voriconazole
   A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure)  Careful assessment of voriconazole effectiveness


Table name:
Table 8: Selected Drug Interactions in Adults
Concomitant Drug Class:
Drug Name
Effect on Concentration of Raltegravir Clinical Comment
Metal-Containing Antacids
aluminum and/or magnesium-containing antacids Coadministration or staggered administration of aluminum and/or magnesium hydroxide-containing antacids and ISENTRESS is not recommended.
Other Agents
rifampin The recommended dosage of ISENTRESS is 800 mg twice daily during coadministration with rifampin. There are no data to guide co-administration of ISENTRESS with rifampin in patients below 18 years of age [see Dosage and Administration (2.1)].


Table name:
Antibiotics Anti-neoplastics Antifungals Anti-inflammatory Drugs Gastrointestinal Agents Immuno-suppressives Other Drugs
ciprofloxacin gentamicin tobramycin vancomycin trimethoprim with sulfamethoxazole melphalan amphotericin B ketoconazole azapropazon colchicine diclofenac naproxen sulindac cimetidine ranitidine tacrolimus fibric acid derivatives (e.g., bezafibrate, fenofibrate) methotrexate


Table name:
Table 7: Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology (12.3)]
* Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg q12h voriconazole to healthy subjects
** Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects
*** Non-Nucleoside Reverse Transcriptase Inhibitors
Drug/Drug Class
(Mechanism of Interaction by the Drug)
Voriconazole Plasma Exposure
(Cmax and AUC τ after
200 mg q12h)
Recommendations for Voriconazole Dosage Adjustment/Comments
Rifampin* and Rifabutin*
(CYP450 Induction)
Significantly Reduced
Contraindicated
Efavirenz (400 mg q24h)**
(CYP450 Induction)
 
Efavirenz (300 mg q24h)**
(CYP450 Induction)
Significantly Reduced
 
 
Slight Decrease in AUCτ
Contraindicated
 
 
When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)** (CYP450 Induction)
 
Low-dose Ritonavir (100 mg q12h)** (CYP450 Induction)
Significantly Reduced
 
 
Reduced
Contraindicated
Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Carbamazepine
(CYP450 Induction)
Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction
Contraindicated
Long Acting Barbiturates
(CYP450 Induction)
Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction
Contraindicated
Phenytoin*
(CYP450 Induction)
Significantly Reduced
Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV  q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg)
St. John’s Wort
(CYP450 inducer; P-gp inducer)
Significantly Reduced
Contraindicated
Oral Contraceptives**
containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)
Increased
Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole** (CYP2C9, CYP2C19 and CYP3A4 Inhibition)
Significantly Increased
Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole.
Other HIV Protease Inhibitors
(CYP3A4 Inhibition)
In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure
 
In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)
No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir
 
Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIs***
(CYP3A4 Inhibition or CYP450 Induction)
In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure)
 
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure)
Frequent monitoring for adverse events and toxicity related to voriconazole
 
 
 
 
Careful assessment of voriconazole effectiveness


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may
result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-
   containing radiographic
   contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which
may result in hyperthyroidism
Amiodarone
Iodide (including iodine-
containing Radiographic
contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase Drugs that may decrease
serum TBG concentration serum TBG concentration
Clofibrate Androgens / Anabolic Steroids
Estrogen-containing oral Asparaginase
   contraceptives Glucocorticoids
Estrogens (oral) Slow-Release Nicotinic Acid
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal
Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake
Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
NITROPRUSSIDE
Para-aminosalicylate sodium
Perphenazine
Resorcinol
 (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 4. Sevelamer Drug Interactions
Oral drugs for which sevelamer did not alter the pharmacokinetics when administered concomitantly
Digoxin
Enalapril
Iron
Metoprolol
Warfarin
Oral drugs that have demonstrated interaction with sevelamer and are to be dosed separately from Renagel
Dosing Recommendations
Ciprofloxacin Take at least 2 hours before or 6 hours after sevelamer
Mycophenolate mofetil Take at least 2 hours before sevelamer


Table name:
 Concomitant Drug Name or Drug Class  Clinical Rationale  Clinical Recommendation
 Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine)  The concomitant use of aripiprazole with strong CYP3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].  With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
 Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)  The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].  With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
 Antihypertensive Drugs  Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.  Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.7)].
 Benzodiazepines(e.g., lorazepam)  The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.7)].  Monitor sedation and blood pressure. Adjust dose accordingly.


Table name:
Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline. Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol, lomefloxacin
  systemic and inhaled mebendazole
amoxicillin medroxyprogesterone
ampicillin, methylprednisolone
  with or without sulbactam metronidazole
atenolol metoprolol
azithromycin nadolol
caffeine, nifedipine
  dietary ingestion nizatidine
cefactor norfloxacin
co-trimoxazole ofloxacin
  (trimethoprim and omeprazole
  sulfamethoxazole) prednisone, prednisolone
diltiazem ranitidine
dirithromycin rifabutin
enflurane roxithromycin
famotidine sorbitol
felodipine   (purgative doses do not
finasteride   inhibit theophylline
hydrocortisone   absorption)
isoflurane sucralfate
isoniazid terbutaline, systemic
isradipine terfenadine
influenza vaccine tetracycline
ketoconazole tocainide


Table name:
Table 25: Clinically Important Drug Interactions with ABILIFY:
Concomitant Drug Name or Drug Class Clinical Rationale Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) The concomitant use of ABILIFY with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of ABILIFY alone [see CLINICAL PHARMACOLOGY (12.3)]. With concomitant use of ABILIFY with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the ABILIFY dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin) The concomitant use of ABILIFY and carbamazepine decreased the exposure of aripiprazole compared to the use of ABILIFY alone [see CLINICAL PHARMACOLOGY (12.3)]. With concomitant use of ABILIFY with a strong CYP3A4 inducer, consider increasing the ABILIFY dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Antihypertensive Drugs Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.8) ].
Benzodiazepines (e.g., lorazepam) The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.8) ]. Monitor sedation and blood pressure. Adjust dose accordingly.


Table name:
Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
Factors
Dosage Adjustment of Aripiprazole tablets
Known CYP2D6 Poor Metabolizers
Administer half of usual dose
KnownCYP2D6Poor Metabolizersand strongCYP3A4 inhibitors
Administer a quarter of usualdose
StrongCYP2D6 or CYP3A4inhibitors
Administerhalf of usual dose
StrongCYP2D6andCYP3A4 inhibitors
Administer a quarter of usualdose
StrongCYP3A4inducers
Double usual doseover 1 to 2 weeks


Table name:
Table 9 Established and Other Potentially Significant Drug Interactions with Ganciclovir
Name of the  
Concomit a nt Drug
 Change in the Concentration of   Ganciclovir or
Concomitant Drug
 Clinical Comment
 Zidovudine ↓ Ganciclovir
↑ Zidovudine
Zidovudine and Valganciclovir each have the potential to cause neutropenia and anemia
 Probenecid ↑ Ganciclovir Patients taking probenecid and Valganciclovir should be monitored for evidence of ganciclovir toxicity
 Mycophenolate
 Mofetil (MMF)
↔ Ganciclovir (in patients with normal renal function)
↔ MMF (in patients with normal renal function)
Patients with renal impairment should be monitored carefully as levels of MMF metabolites and ganciclovir may increase
 Didanosine ↓ Ganciclovir
↑ Didanosine
Patients should be closely monitored for didanosine toxicity


Table name:
Drug Interactions Associated with Increased Risk of  Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice Avoid grapefruit juice


Table name:
Table 18. Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
* Change relative to reference
Coadministered Drug
Dosing Schedule
Effect on Active
Moiety (Risperidone +
9-Hydroxy-
Risperidone Ratio*)
Risperidone
Dose
Recommendation
Coadministered
Drug
Risperidone
AUC
Cmax
Enzyme (CYP2D6)
Inhibitors
 
 
 
 
 
Fluoxetine
20 mg/day
2 or 3 mg twice daily
1.4
1.5
Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine
10 mg/day
4 mg/day
1.3
-
Re-evaluate dosing. Do not exceed 8 mg/day
 
20 mg/day
4 mg/day
1.6
-
 
40 mg/day
4 mg/day
1.8
-
Enzyme (CYP3A/
PgP inducers)
Inducers
 
 
 
 
 
Carbamazepine
573 ± 168 mg/day
3 mg twice daily
0.51
0.55
Titrate dose upwards. Do not exceed twice the patient's usual dose
Enzyme (CYP3A)
Inhibitors
 
 
 
 
 
Ranitidine
150 mg twice daily
1 mg single dose
1.2
1.4
Dose adjustment not needed
Cimetidine
400 mg twice daily
1 mg single dose
1.1
1.3
Dose adjustment not needed
Erythromycin
500 mg four times daily
1 mg single dose
1.1
0.94
Dose adjustment not needed
Other Drugs
 
 
 
 
 
Amitriptyline
50 mg twice daily
3 mg twice daily
1.2
1.1
Dose adjustment not needed


Table name:
Bleeding times
Clinical Impact: Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention: This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact: The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention: Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact: Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention: This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.


Table name:
Table 3       Effects of Other Drugs on Paroxetine
Concomitant
Drug Name


Effect of Concomitant Drug
on Paroxetine


Clinical Recommendations

Phenobarbital

Decreased paroxetine exposure
 


Phenytoin

Decreased paroxetine exposure

 


Fosamprenavir/
Ritonavir


Decreased plasma concentration
of paroxetine
No dose adjustment for BRISDELLE.

Monitor clinical effect of BRISDELLE.
Cimetidine Increased plasma concentration
of paroxetine

 


Table name:
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine Decreased lamotrigine concentrations approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? carbamazepine epoxide May increase carbamazepine epoxide levels.
Lopinavir/ritonavir ↓ lamotrigine Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir ↓ lamotrigine Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine Increased lamotrigine concentrations slightly more than 2-fold.
? valproate There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.


Table name:
Drugs That are Affected by Ciprofloxacin
Drug(s) Recommendation Comments
Tizanidine Contraindicated Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)]
Theophylline Avoid Use (Plasma Exposure Likely to be Increased and Prolonged) Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions (5.9)].
Drugs Known to Prolong QT Interval Avoid Use Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.11) and Use in Specific Populations (8.5)].
Oral antidiabetic drugs Use with caution Glucose-lowering effect potentiated Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs [see Adverse Reactions (6.1)].
Phenytoin Use with caution Altered serum levels of phenytoin (increased and decreased) To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co­-administration of ciprofloxacin with phenytoin.
Cyclosporine Use with caution (transient elevations in serum creatinine) Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs Use with caution (Increase in anticoagulant effect) The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole Use with caution Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co­administration with ciprofloxacin [see Warnings and Precautions (5.16)].
Clozapine Use with caution Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs Use with caution Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil Use with caution
Two-fold increase in exposure
Monitor for sildenafil toxicity [see Clinical Pharmacology (12.3)].
Duloxetine Avoid Use
Five-fold increase in duloxetine exposure
If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine
Derivatives
Use with caution Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Reduced clearance resulting in elevated levels and prolongation of serum half-life
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products) Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation- containing products administration [see Dosage and Administration (2.4)]. Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Potentiation of ciprofloxacin toxicity may occur.
Probenecid Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)


Table name:
Factors
Dosage Adjustment of Aripiprazole tablets
Known CYP2D6 Poor Metabolizers
Administer half of usual dose
KnownCYP2D6Poor Metabolizersand strongCYP3A4 inhibitors
Administer a quarter of usualdose
StrongCYP2D6 or CYP3A4inhibitors
Administerhalf of usual dose
StrongCYP2D6andCYP3A4 inhibitors
Administer a quarter of usualdose
StrongCYP3A4inducers
Double usual doseover 1 to 2 weeks


Table name:
Table 3: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 10 and 20 mg in BPH patients on stable alpha-blocker therapy with tamsulosin 0.4 or 0.8 mg daily (Study 2)
Vardenafil 10 mg
Placebo-subtracted
Vardenafil 20 mg
Placebo-subtracted
Standing SBP -4 (-6.8, -0.3) -4 (-6.8, -1.4)
Supine SBP -5 (-8.2, -0.8) -4 (-6.3, -1.8)


Table name:
Summary of AED interactions with topiramate (7.1).
AED Co-administered AED Concentration Topiramate Concentration
Phenytoin NC or 25% increasea 48% decrease
Carbamazepine (CBZ) NC 40% decrease
CBZ epoxideb NC NE
Valproic acid 11% decrease 14% decrease
Phenobarbital NC NE
Primidone NC NE
Lamotrigine NC at TPM doses up to 400mg/day 13% decrease


Table name:
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine

↓ levonorgestrel
Decreased lamotrigine concentrations approximately 50%.
Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide ↓ lamotrigine


? carbamazepine epoxide
Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
May increase carbamazepine epoxide levels.
Lopinavir/ritonavir ↓ lamotrigine Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir ↓ lamotrigine Decreased lamotrigine AUC approximately 32%.
Phenobarbital/Primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine

? valproate
Increased lamotrigine concentrations slightly more than 2-fold.
There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.


Table name:
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin dailyFor patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice Avoid grapefruit juice


Table name:
Table 8: Clinically Significant Drug Interactions with Clarithromycin
Drugs That Are Affected By Clarithromycin
Drug(s) with Pharmacokinetics Affected by Clarithromycin Recommendation Comments
Antiarrhythmics:


 
Disopyramide
Quinidine
Dofetilide
Amiodarone
Sotalol
Procainamide
Not Recommended Disopyramide, Quinidine: There have been postmarketing reports of torsades de pointes occurring with concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QTc prolongation during coadministration of clarithromycin with these drugs [see Warnings and Precautions (5.3)].

Serum concentrations of these medications should also be monitored. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with disopyramide and quinidine.

There have been postmarketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide. Therefore, blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide.


Digoxin Use With Caution Digoxin: Digoxin is a substrate for P-glycoprotein (Pgp) and clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are co-administered, inhibition of Pgp by clarithromycin may lead to increased exposure of digoxin. Elevated digoxin serum concentrations in patients receiving clarithromycin and digoxin concomitantly have been reported in postmarketing surveillance. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Monitoring of serum digoxin concentrations should be considered, especially for patients with digoxin concentrations in the upper therapeutic range.


Oral Anticoagulants:


   
Warfarin Use With Caution Oral anticoagulants: Spontaneous reports in the postmarketing period suggest that concomitant administration of clarithromycin and oral anticoagulants may potentiate the effects of the oral anticoagulants. Prothrombin times should be carefully monitored while patients are receiving clarithromycin and oral anticoagulants simultaneously [see Warnings and Precautions (5.4)].


Antiepileptics:


   
Carbamazepine Use With Caution Carbamazepine: Concomitant administration of single doses of clarithromycin and carbamazepine has been shown to result in increased plasma concentrations of carbamazepine. Blood level monitoring of carbamazepine may be considered. Increased serum concentrations of carbamazepine were observed in clinical trials with clarithromycin. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with carbamazepine.


Antifungals:


 
Itraconazole Use With Caution Itraconazole: Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when administered concomitantly (see also Itraconazole under “Drugs That Affect Clarithromycin” in the table below). Clarithromycin may increase the plasma concentrations of itraconazole. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions.


Fluconazole No Dose Adjustment


Fluconazole: [see Pharmacokinetics (12.3)]
Anti-Gout Agents:


 
Colchicine (in patients with renal or hepatic impairment)


Colchicine (in patients with normal renal and hepatic function)
Contraindicated




Use With Caution
Colchicine: Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. The dose of colchicine should be reduced when co-administered with clarithromycin in patients with normal renal and hepatic function [see Contraindications (4.4) and Warnings and Precautions (5.4)].


Antipsychotics:


 
Pimozide Contraindicated Pimozide: [See Contraindications (4.2)]


Quetiapine   Quetiapine: Quetiapine is a substrate for CYP3A4, which is inhibited by clarithromycin. Co-administration with clarithromycin could result in increased quetiapine exposure and possible quetiapine related toxicities. There have been postmarketing reports of somnolence, orthostatic hypotension, altered state of consciousness, neuroleptic malignant syndrome, and QT prolongation during concomitant administration. Refer to quetiapine prescribing information for recommendations on dose reduction if co-administered with CYP3A4 inhibitors such as clarithromycin.


Antispasmodics:


   
Tolterodine (patients deficient in CYP2D6 activity) Use With Caution Tolterodine: The primary route of metabolism for tolterodine is via CYP2D6. However, in a subset of the population devoid of CYP2D6, the identified pathway of metabolism is via CYP3A. In this population subset, inhibition of CYP3A results in significantly higher serum concentrations of tolterodine. Tolterodine 1 mg twice daily is recommended in patients deficient in CYP2D6 activity (poor metabolizers) when co-administered with clarithromycin.


Antivirals:


   
Atazanavir Use With Caution Atazanavir: Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction (see Atazanavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)].


Saquinavir (in patients with decreased renal function)   Saquinavir: Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A and there is evidence of a bi-directional drug interaction (see Saquinavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)].


Ritonavir
Etravirine
  Ritonavir, Etravirine: (see Ritonavir and Etravirine under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)].


Maraviroc   Maraviroc: Clarithromycin may result in increases in maraviroc exposures by inhibition of CYP3A metabolism. See Selzentry® prescribing information for dose recommendation when given with strong CYP3A inhibitors such as clarithromycin.


Boceprevir (in patients with normal renal function)

Didanosine
No Dose Adjustment Boceprevir: Both clarithromycin and boceprevir are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when co-administered. No dose adjustments are necessary for patients with normal renal function (see Victrelis® prescribing information).


Zidovudine   Zidovudine: Simultaneous oral administration of clarithromycin immediate-release tablets and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine concentrations. Administration of clarithromycin and zidovudine should be separated by at least two hours [see Pharmacokinetics (12.3)].

The impact of co-administration of clarithromycin extended-release tablets or granules and zidovudine has not been evaluated.


Calcium Channel Blockers:


   
Verapamil Use With Caution Verapamil: Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent verapamil, [see Warnings and Precautions (5.4)].


Amlodipine
Diltiazem


  Amlodipine, Diltiazem: [See Warnings and Precautions (5.4)]
Nifedipine   Nifedipine: Nifedipine is a substrate for CYP3A. Clarithromycin and other macrolides are known to inhibit CYP3A. There is potential of CYP3A-mediated interaction between nifedipine and clarithromycin. Hypotension and peripheral edema were observed when clarithromycin was taken concomitantly with nifedipine [see Warnings and Precautions (5.4)].


Ergot Alkaloids:


   
Ergotamine
Dihydroergotamine
Contraindicated Ergotamine, Dihydroergotamine: Postmarketing reports indicate that coadministration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system [see Contraindications (4.6)].


Gastroprokinetic Agents:


   
Cisapride Contraindicated Cisapride: [See Contraindications (4.2)]


HMG-CoA Reductase Inhibitors:


   
Lovastatin
Simvastatin
Contraindicated Lovastatin, Simvastatin, Atorvastatin, Pravastatin, Fluvastatin: [See Contraindications (4.5) and Warnings and Precautions (5.4)]

Atorvastatin
Pravastatin


Use With Caution  
Fluvastatin

No Dose Adjustment


 
Hypoglycemic Agents:


   
Nateglinide
Pioglitazone
Repaglinide
Rosiglitazone


Use With Caution Nateglinide, Pioglitazone, Repaglinide, Rosiglitazone: [See Warnings and Precautions (5.4) and Adverse Reactions (6.2)]

Insulin   Insulin: [See Warnings and Precautions (5.4) and Adverse Reactions (6.2)]


Immunosuppressants:


   
Cyclosporine Use With Caution Cyclosporine: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with cyclosporine.


Tacrolimus   Tacrolimus: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with tacrolimus.


Phosphodiesterase inhibitors:


   
Sildenafil
Tadalafil
Vardenafil
Use With Caution Sildenafil, Tadalafil, Vardenafil: Each of these phosphodiesterase inhibitors is primarily metabolized by CYP3A, and CYP3A will be inhibited by concomitant administration of clarithromycin. Co-administration of clarithromycin with sildenafil, tadalafil, or vardenafil will result in increased exposure of these phosphodiesterase inhibitors. Co-administration of these phosphodiesterase inhibitors with clarithromycin is not recommended. Increased systemic exposure of these drugs may occur with clarithromycin; reduction of dosage for phosphodiesterase inhibitors should be considered (see their respective prescribing information).


Proton Pump Inhibitors:


   
Omeprazole No Dose Adjustment Omeprazole: The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when coadministered with clarithromycin as a result of increased omeprazole exposures [see Pharmacokinetics (12.3)] (see also Omeprazole under “Drugs That Affect Clarithromycin” in the table below).


Xanthine Derivatives:


   
Theophylline Use With Caution Theophylline: Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serum theophylline concentrations [see Pharmacokinetics (12.3)]. Monitoring of serum theophylline concentrations should be considered for patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range.


Triazolobenzodiazepines and Other Related Benzodiazepines:


   
Midazolam Use With Caution Midazolam: When oral midazolam is co-administered with clarithromycin, dose adjustments may be necessary and possible prolongation and intensity of effect should be anticipated [see Warnings and Precautions (5.4) and Pharmacokinetics (12.3)].


Alprazolam
Triazolam
  Triazolam, Alprazolam: Caution and appropriate dose adjustments should be considered when triazolam or alprazolam is co-administered with clarithromycin. There have been postmarketing reports of drug interactions and central nervous system (CNS) effects (e.g., somnolence and confusion) with the concomitant use of clarithromycin and triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested.

In postmarketing experience, erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines.


Temazepam
Nitrazepam
Lorazepam
No Dose Adjustment Temazepam, Nitrazepam, Lorazepam: For benzodiazepines which are not metabolized by CYP3A (e.g., temazepam, nitrazepam, lorazepam), a clinically important interaction with clarithromycin is unlikely.


Cytochrome P450 Inducers:


   
Rifabutin Use With Caution Rifabutin: Concomitant administration of rifabutin and clarithromycin resulted in an increase in rifabutin, and decrease in clarithromycin serum levels together with an increased risk of uveitis (see Rifabutin under “Drugs That Affect Clarithromycin” in the table below).


Other Drugs Metabolized by CYP3A:


   
Alfentanil
Bromocriptine
Cilostazol
Methylprednisole
Vinblastine
Phenobarbital
St. John’s Wort


Use With Caution There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with alfentanil, methylprednisolone, cilostazol, bromocriptine, vinblastine, phenobarbital, and St. John’s Wort.
Other Drugs Metabolized by CYP450 Isoforms Other than CYP3A:


   
Hexobarbital
Phenytoin
Valproate
Use With Caution There have been postmarketing reports of interactions of clarithromycin with drugs not thought to be metabolized by CYP3A, including hexobarbital, phenytoin, and valproate.


Drugs that Affect Clarithromycin
Drug(s) that Affect the Pharmacokinetics of Clarithromycin Recommendation Comments
Antifungals:


   
Itraconazole

Use With Caution Itraconazole: Itraconazole may increase the plasma concentrations of clarithromycin. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions (see also Itraconazole under “Drugs That Are Affected By Clarithromycin” in the table above).


Antivirals:


   
Atazanavir Use With Caution Atazanavir: When clarithromycin is co-administered with atazanavir, the dose of clarithromycin should be decreased by 50% [see Clinical Pharmacology (12.3)].

Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with atazanavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium complex. Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.


Ritonavir (in patients with decreased renal function)   Ritonavir: Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with ritonavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium [see Pharmacokinetics (12.3)].

Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.


Saquinavir (in patients with decreased renal function)   Saquinavir: When saquinavir is co-administered with ritonavir, consideration should be given to the potential effects of ritonavir on clarithromycin (refer to ritonavir above) [see Pharmacokinetics (12.3)].


Etravirine   Etravirine: Clarithromycin exposure was decreased by etravirine; however, concentrations of the active metabolite, 14-OH-clarithromycin, were increased. Because 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered; therefore alternatives to clarithromycin should be considered for the treatment of MAC.


Saquinavir (in patients with normal renal function) No Dose Adjustment  
Ritonavir (in patients with normal renal function)


   
Proton Pump Inhibitors:


   
Omeprazole Use With Caution Omeprazole: Clarithromycin concentrations in the gastric tissue and mucus were also increased by concomitant administration of omeprazole [see Pharmacokinetics (12.3)].


Miscellaneous Cytochrome P450 Inducers:


 
Efavirenz
Nevirapine
Rifampicin
Rifabutin
Rifapentine
Use With Caution Inducers of CYP3A enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine will increase the metabolism of clarithromycin, thus decreasing plasma concentrations of clarithromycin, while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. Alternative antibacterial treatment should be considered when treating patients receiving inducers of CYP3A. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with rifabutin (see Rifabutin under “Drugs That Are Affected By Clarithromycin” in the table above).




Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
↓= Decreased (induces lamotrigine glucuronidation).
↑= Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine Decreased lamotrigine levels approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? CBZ epoxide May increase CBZ epoxide levels.
Phenobarbital/Primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT) ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine Increased lamotrigine concentrations slightly more than 2-fold.
? valproate Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
AED Coadministered AED Concentration Topiramate Concentration
Phenytoin
NC or 25% increase Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
48% decrease


Carbamazepine (CBZ)
NC
40% decrease
CBZ epoxide Is not administered but is an active metabolite of carbamazepine.
NC
NE
Valproic acid
11% decrease
14% decrease
Phenobarbital
NC
NE
Primidone
NC
NE
Lamotrigine
NC at TPM doses up to 400 mg/day
13% decrease


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Table 7 Summary of AED Interactions with Oxcarbazepine Tablets, USP
AED Coadministered Dose of AED
(mg/day)
Oxcarbazepine Tablets Dose
(mg/day)
Influence of Oxcarbazepine Tablets on AED Concentration
(Mean Change, 90% Confidence Interval)
Influence of AED on MHD Concentration
(Mean Change, 90% Confidence Interval)
Carbamazepine 400-2000 900 nc nc denotes a mean change of less than 10% 40% decrease
[CI: 17% decrease, 57% decrease]
Phenobarbital 100-150 600-1800 14% increase
[CI: 2% increase, 24% increase]
25% decrease
[CI: 12% decrease, 51% decrease]
Phenytoin 250-500 600-1800
>1200-2400
nc , Pediatrics up to 40% increase Mean increase in adults at high oxcarbazepine tablets, USP doses
[CI: 12% increase, 60% increase]
30% decrease
[CI: 3% decrease, 48% decrease]
Valproic acid 400-2800 600-1800 nc 18% decrease
[CI: 13% decrease, 40% decrease]


Table name:
Interacting Drug Interaction
Drugs known to prolong QT interval (e.g., Class IA and Class III antiarrhythmic agents). QUALAQUIN prolongs QT interval, ECG abnormalities including QT prolongation and Torsades de Pointes. Avoid concomitant use (5.3).
Other antimalarials (e.g., halofantrine, mefloquine). ECG abnormalities including QT prolongation. Avoid concomitant use (5.3, 7.2).
CYP3A4 inducers or inhibitors Alteration in plasma quinine concentration. Monitor for lack of efficacy or increased adverse events of quinine (7.1).
CYP3A4 and CYP2D6 substrates Quinine is an inhibitor of CYP3A4 and CYP2D6. Monitor for lack of efficacy or increased adverse events of the co-administered drug (7.2).
Digoxin Increased digoxin plasma concentration (5.8, 7.1).


Table name:
Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.*
albuterol, systemic and inhaledlomefloxacin
amoxicillinmebendazole
ampicillin, with or without sulbactammedroxyprogesterone
atenololmethylprednisolone
azithromycinmetronidazole
caffeine, dietary ingestionmetoprolol
cefaclornadolol
co-trimoxazole (trimethoprim and sulfamethoxazole)nifedipine
diltiazemnizatidine
dirithromycinnorfloxacin
enfluraneofloxacin
famotidineomeprazole
felodipineprednisone, prednisolone
finasterideranitidine
hydrocortisonerifabutin
isofluraneroxithromycin
isoniazidsorbitol (purgative doses do not inhibit theophylline absorption)
isradipinesucralfate
influenza vaccineterbutaline, systemic
ketoconazoleterfenadine
tetracycline
tocainide
* Refer to PRECAUTIONS, Drug Interactions for information regarding table.


Table name:
Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) VIAGRA 100 mg
Supine 7.9 (4.6, 11.1)
Standing

4.3 (-1.8,10.3)



Table name:
Table II. Clinically Significant Drug Interactions With Theophylline*
Drug Type Of Interaction Effect**
Adenosine Theophylline blocks adenosine receptors. Higher doses of adenosine may be required to achieve desired effect.
Alcohol A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours. 30% increase
Allopurinol Decreases theophylline clearance at allopurinol doses ≥600 mg/day. 25% increase
Aminoglutethimide Increases theophylline clearance by induction of microsomal enzyme activity. 25% decrease
Carbamazepine Similar to aminoglutethimide. 30% decrease
Cimetidine Decreases theophylline clearance by inhibiting cytochrome P450 1A2. 70% increase
Ciprofloxacin Similar to cimetidine. 40% increase
Clarithromycin Similar to erythromycin. 25% increase
Diazepam Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram Decreases theophylline clearance by inhibiting hydroxylation and demethylation. 50% increase
Enoxacin Similar to cimetidine. 300% increase
Ephedrine Synergistic CNS effects. Increased frequency of nausea, nervousness, and insomnia.
Erythromycin Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3. 35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown. 30% increase
Flurazepam Similar to diazepam. Similar to diazepam.
Fluvoxamine Similar to cimetidine. Similar to cimetidine.
Halothane Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines. Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-A Decreases theophylline clearance. 100% increase
Isoproterenol (I.V.) Increases theophylline clearance. 20% decrease
Ketamine Pharmacologic May lower theophylline seizure threshold.
Lithium Theophylline increases renal lithium clearance. Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam Similar to diazepam. Similar to diazepam.
Methotrexate (MTX) Decreases theophylline clearance. 20% increase after low dose MTX, higher dose MTX may have a greater effect.
Mexiletine Similar to disulfiram. 80% increase
Midazolam Similar to diazepam. Similar to diazepam.
Moricizine Increases theophylline clearance. 25% decrease
Pancuronium Theophylline may antagonize nondepolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition. Larger dose of pancuronium may be required to achieve neuromuscular blockade.
Pentoxifylline Decreases theophylline clearance. 30% increase
Phenobarbital (PB) Similar to aminoglutethimide. 25% decrease after two weeks of concurrent Phenobarbital.
Phenytoin Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption. Serum theophylline and phenytoin concentrations decrease about 40%.
Propafenone Decreases theophylline clearance and pharmacologic interaction. 40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Propranolol Similar to cimetidine and pharmacologic interaction. 100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Rifampin Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity. 20 - 40% decrease
Sulfinpyrazone Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline. 20% decrease
Tacrine Similar to cimetidine, also increases renal clearance of theophylline. 90% increase
Thiabendazole Decreases theophylline clearance. 190% increase
Ticlopidine Decreases theophylline clearance. 60% increase
Troleandomycin Similar to erythromycin. 33 - 100% increase depending on troleandomycin dose.
Verapamil Similar to disulfiram. 20% increase
* Refer to PRECAUTIONS , Drug Interactions for further information regarding table.
** Average effect on steady-state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.


Table name:
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Table 4: Clinically Relevant Interactions Affecting Omeprazole When Co-Administered with Other Drugs
CYP2C19 or CYP3A4 Inducers
Clinical Impact:
Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology ( 12.3)].
Intervention:
St. John’s Wort, rifampin: Avoid concomitant use with omeprazole [see Warnings and Precautions ( 5.9)].
Ritonavir-containing products: see prescribing information for specific drugs.
CYP2C19 or CYP3A4 Inhibitors
Clinical Impact:
Increased exposure of omeprazole [see Clinical Pharmacology ( 12.3)].
Intervention:
Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered.
 
See prescribing information for voriconazole.


Table name:
Drug Description
Heparin Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients
Pyrazinamide Inhibits pyrazinamide-induced hyperuricemia
Uricosuric Agents Effect of probenecid, sulfinpyrazone and phenylbutazone inhibited


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.10, 7.3)


Table name:
Table 5. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
↓ = Decreased (induces lamotrigine glucuronidation).
↑ = Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine Decreased lamotrigine concentrations approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine
and carbamazepine epoxide
↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? carbamazepine epoxide May increase carbamazepine epoxide levels.
Lopinavir/ritonavir ↓ lamotrigine Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir ↓ lamotrigine Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine Increased lamotrigine concentrations slightly more than 2-fold.
? valproate There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.


Table name:
TABLE 2. Mean (± S.D.) Pharmacokinetic Parameters for Estradiol, Estrone, and Equilin Following Coadministration of Conjugated Estrogens 0.625 mg and PROMETRIUM Capsules 200 mg for 12 Days to Postmenopausal Women
a Total estrogens is the sum of conjugated and unconjugated estrogen.
Conjugated Estrogens Conjugated Estrogens plus PROMETRIUM Capsules
Drug Cmax
(ng/mL)
Tmax
(hr)
AUC(0-24h)
(ng × h/mL)
Cmax
(ng/mL)
Tmax
(hr)
AUC(0-24h)
(ng × h/mL)
Estradiol 0.037
± 0.048
12.7
± 9.1
0.676
± 0.737
0.030
± 0.032
17.32
± 1.21
0.561
± 0.572
Estrone
Total a
3.68
± 1.55
10.6
± 6.8
61.3
± 26.36
4.93
± 2.07
7.5
± 3.8
85.9
± 41.2
Equilin
Total a
2.27
± 0.95
6.0
± 4.0
28.8
± 13.0
3.22
± 1.13
5.3
± 2.6
38.1
± 20.2


Table name:
Table 18Summary of Effect of Coadministered Drugs on Exposure to Active Moiety(Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients withSchizophrenia
*Change relative to reference
Coadministered Drug
Dosing Schedule

Effect on Active
Moiety
(Risperidone + 9-
Hydroxy-
Risperidone (Ratio*)

Risperidone Dose
Recommendation

Coadministered Drug
Risperidone
AUC
C m a x

Enzyme (CYP2D6) 
Inhibitors 





Fluoxetine 
20 mg/day
2 or 3 mg twice
daily
1.4
1.5
Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine 
10 mg/day
4 mg/day
1.3
-
Re-evaluate dosing. 

20 mg/day
4 mg/day
1.6
-
Do not exceed 8 mg/day

40 mg/day
4 mg/day
1.8
-

Enzyme (CYP3A/ 
PgP inducers) 





Carbamazepine 
573 ± 168 mg/day
3 mg twice daily
0.51
0.55
Titrate dose upwards.
Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) 
Inhibitors 





Ranitidine 
150 mg twice daily
1 mg single dose
1.2
1.4
Dose adjustment not
needed
Cimetidine 
400 mg twice daily
1 mg single dose
1.1
1.3
Dose adjustment not
needed
Erythromycin 
500 mg four times
daily
1 mg single dose
1.1
0.94
Dose adjustment not
needed
Other Drugs 





Amitriptyline 
50 mg twice daily
3 mg twice daily
1.2
1.1
Dose adjustment not
needed


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C Protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Table 2: Clinically Relevant Interactions Affecting Drugs Co-Administered with Rabeprazole Sodium Delayed-Release Tablets

Antiretrovirals

Clinical Impact:

The effect of PPI on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir, and nelfinavir) when used concomitantly with rabeprazole may reduce antiviral effect and promote the development of drug resistance. Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with rabeprazole may increase toxicity. There are other antiretroviral drugs which do not result in clinically relevant interactions with rabeprazole.

Intervention: 

Rilpivirine-containing products: Concomitant use with rabeprazole sodium delayed-release tablets is contraindicated [see Contraindications (4)]. See prescribing information.
Atazanavir: See prescribing information for atazanavir for dosing information.
Nelfinavir: Avoid concomitant use with rabeprazole sodium delayed-release tablets. See prescribing information for nelfinavir.
Saquinavir: See the prescribing information for saquinavir and monitor for potential saquinavir toxicities.
Other antiretrovirals: See prescribing information.

Warfarin  

Clinical Impact:

Increased INR and prothrombin time in patients receiving PPIs, including rabeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death [see Warnings and Precautions (5.2)].

Intervention:

Monitor INR and prothrombin time. Dose adjustment of warfarin may be needed to maintain target INR range. See prescribing information for warfarin.

Methotrexate

Clinical Impact:
 

Concomitant use of rabeprazole with methotrexate (primarily at high dose) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of methotrexate with PPIs have been conducted [see Warnings and Precautions (5.9)].

Intervention: 

A temporary withdrawal of rabeprazole sodium delayed-release tablets may be considered in some patients receiving high dose methotrexate administration.

Digoxin

Clinical Impact:

Potential for increased exposure of digoxin [see Clinical Pharmacology (12.3)].

Intervention:

Monitor digoxin concentrations. Dose adjustment of digoxin may be needed to maintain therapeutic drug concentrations. See prescribing information for digoxin.

Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole, itraconazole)

Clinical Impact:

Rabeprazole can reduce the absorption of drugs due to its effect on reducing intragastric acidity.

Intervention:

Mycophenolate mofetil (MMF): Co-administration of PPIs in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving PPIs and MMF. Use rabeprazole sodium delayed-release tablets with caution in transplant patients receiving MMF.

See the prescribing information for other drugs dependent on gastric pH for absorption.

Combination Therapy with Clarithromycin and Amoxicillin

Clinical Impact:

Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated.

Amoxicillin also has drug interactions.

Intervention:

See Contraindications and Warnings and Precautions in prescribing information for clarithromycin.

See Drug Interactions in prescribing information for amoxicillin.


Table name:
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine Decreased lamotrigine concentrations approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? carbamazepine epoxide May increase carbamazepine epoxide levels.
Lopinavir/ritonavir ↓ lamotrigine Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir ↓ lamotrigine Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine Increased lamotrigine concentrations slightly more than 2-fold.
? valproate There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
 Interacting Agents  Prescribing Recommendations
  Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol  Contraindicated with simvastatin
 Verapamil, diltiazem, dronedarone  Do not exceed 10 mg simvastatin daily
 Amiodarone, amlodipine, ranolazine  Do not exceed 20 mg simvastatin daily
 Grapefruit juice  Avoid grapefruit juice


Table name:
Table 9. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class:
Drug Name
Effect on Concentration of Lopinavir or Concomitant Drug Clinical Comment
*   see Clinical Pharmacology (12.3) for Magnitude of Interaction.
HIV-1 Antiviral Agents
Non-nucleoside Reverse Transcriptase Inhibitors:
efavirenz*,
nevirapine*
↓ lopinavir KALETRA dose increase is recommended in all patients [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
Increasing the dose of KALETRA tablets to 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) twice daily co-administered with efavirenz resulted in similar lopinavir concentrations compared to KALETRA tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz.
Increasing the dose of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice daily co-administered with efavirenz resulted in significantly higher lopinavir plasma concentrations compared to KALETRA tablets 400/100 mg twice daily without efavirenz.
KALETRA should not be administered once daily in combination with efavirenz or nevirapine.
[see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
Non-nucleoside Reverse Transcriptase Inhibitor:
delavirdine
↑ lopinavir Appropriate doses of the combination with respect to safety and efficacy have not been established.
Nucleoside Reverse Transcriptase Inhibitor:
didanosine
KALETRA tablets can be administered simultaneously with didanosine without food.
For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food).
Nucleoside Reverse Transcriptase Inhibitor:
tenofovir
↑ tenofovir KALETRA increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir.
Nucleoside Reverse Transcriptase Inhibitor:
abacavir
zidovudine
↓ abacavir
↓ zidovudine
KALETRA induces glucuronidation; therefore, KALETRA has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown.
HIV-1 Protease Inhibitor:
amprenavir*
↑ amprenavir
↓ lopinavir
KALETRA should not be administered once daily in combination with amprenavir.
[see Dosage and Administration (2.1)].
HIV-1 Protease Inhibitor:
fosamprenavir/ritonavir
↓ amprenavir
↓ lopinavir
An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor:
indinavir*
↑ indinavir Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily [see Clinical Pharmacology (12.3)]. KALETRA once daily has not been studied in combination with indinavir.
HIV-1 Protease Inhibitor:
nelfinavir*
↑ nelfinavir
↑ M8 metabolite of nelfinavir
↓ lopinavir
KALETRA should not be administered once daily in combination with nelfinavir.
[see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].

HIV-1 Protease Inhibitor:
ritonavir*
↑ lopinavir Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor:
saquinavir*
↑ saquinavir The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily.
KALETRA once daily has not been studied in combination with saquinavir.
HIV-1 Protease Inhibitor:
tipranavir
↓ lopinavir AUC and Cmin KALETRA should not be administered with tipranavir (500 mg twice daily) co-administered with ritonavir (200 mg twice daily).
HIV CCR5 – antagonist: maraviroc ↑ maraviroc Concurrent administration of maraviroc with KALETRA will increase plasma levels of maraviroc. When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for Selzentry® (maraviroc).
Other Agents
Antiarrhythmics:
amiodarone,
bepridil,
lidocaine (systemic), and
quinidine
↑ antiarrhythmics Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA.
Anticancer Agents: vincristine
vinblastine
↑ anticancer agents Concentrations of vincristine or vinblastine may be increased when co-administered with lopinavir/ritonavir (KALETRA) resulting in the potential for increased adverse events usually associated with these anticancer agents.

Consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when lopinavir/ritonavir ( KALETRA) is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor.
Anticoagulant:
warfarin
Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants:
carbamazepine,
phenobarbital,
phenytoin
↓ lopinavir
↓ phenytoin
KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution.
KALETRA should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin.

In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA.
Antidepressant:
bupropion
↓ bupropion
↓ active metabolite,
hydroxybupropion
Concurrent administration of bupropion with KALETRA may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion.
Antidepressant:
trazodone
↑ trazodone Concomitant use of trazodone and KALETRA may increase concentrations of trazodone. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered.
Anti-infective:
clarithromycin
↑ clarithromycin For patients with renal impairment, the following dosage adjustments should be considered: For patients with CLCR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients with CLCR < 30 mL/min the dose of clarithromycin should be decreased by 75%.
No dose adjustment for patients with normal renal function is necessary.
Antifungals:
ketoconazole*,
itraconazole,
voriconazole
↑ ketoconazole
↑ itraconazole
↓ voriconazole
High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended.
Co-administration of voriconazole with KALETRA has not been studied. However, a study has been shown that administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%; therefore, co-administration of KALETRA and voriconazole may result in decreased voriconazole concentrations and the potential for decreased voriconazole effectiveness and should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Otherwise, alternative antifungal therapies should be considered in these patients.
Antimycobacterial:
rifabutin*
↑ rifabutin and rifabutin metabolite Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary.
Antimycobacterial:
rifampin
↓ lopinavir May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents. A study evaluated combination of rifampin 600 mg once daily, with KALETRA 800/200 mg twice daily or KALETRA 400/100 mg + ritonavir 300 mg twice daily. Pharmacokinetic and safety results from this study do not allow for a dose recommendation. Nine subjects (28%) experienced a ≥ grade 2 increase in ALT/AST, of which seven (21%) prematurely discontinued study per protocol. Based on the study design, it is not possible to determine whether the frequency or magnitude of the ALT/AST elevations observed is higher than what would be seen with rifampin alone. [see Clinical Pharmacology (12.3) for magnitude of interaction].
Antiparasitic:
atovaquone
↓ atovaquone Clinical significance is unknown; however, increase in atovaquone doses may be needed.
Benzodiazepines: parenterally administered midazolam ↑ midazolam Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, KALETRA should not be given with orally administered midazolam [see Contraindications (4)]. If KALETRA is coadministered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.
Calcium Channel Blockers, dihydropyridine:
e.g., felodipine,
nifedipine,
nicardipine
↑ dihydropyridine calcium channel blockers Caution is warranted and clinical monitoring of patients is recommended.
Corticosteroid:
dexamethasone
↓ lopinavir Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly.
disulfiram/metronidazole KALETRA oral solution contains alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).
PDE5 inhibitors:
sildenafil,
tadalafil,
vardenafil
↑ sildenafil
↑ tadalafil
↑ vardenafil
Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs is expected to substantially increase their concentrations and may result in an increase in associated adverse reactions including hypotension, syncope, visual changes and prolonged erection. It is recommended not to exceed the following doses: Sildenafil: 25 mg every 48 hours Tadalafil: 10 mg every 72 hours Vardenafil: 2.5 mg every 72 hours
HMG-CoA Reductase Inhibitors:
atorvastatin
rosuvastatin
↑ atorvastatin
↑ rosuvastatin
Use lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin or fluvastatin in combination with KALETRA.
Immunosuppressants:
cyclosporine,
tacrolimus,
rapamycin
↑ immunosuppressants Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA.
Inhaled Steroid:
fluticasone
↑ fluticasone Concomitant use of fluticasone propionate and KALETRA may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during post-marketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Co-administration of fluticasone propionate and KALETRA is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effect.
Narcotic Analgesic:
methadone*
↓ methadone Dosage of methadone may need to be increased when co-administered with KALETRA.
Contraceptive:
ethinyl estradiol*
↓ ethinyl estradiol Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended.


Table name:
TABLE 2. Mean (± S.D.) Pharmacokinetic Parameters for Estradiol, Estrone, and Equilin Following Coadministration of Conjugated Estrogens 0.625 mg and Progesterone Capsules 200 mg for 12 Days to Postmenopausal Women
a Total estrogens is the sum of conjugated and unconjugated estrogen.
  Conjugated Estrogens Conjugated Estrogens plus Progesterone Capsules
Drug Cmax
(ng/mL)
Tmax
(hr)
AUC(0-24h)
(ng × h/mL)
Cmax
(ng/mL)
Tmax
(hr)
AUC(0-24h)
(ng × h/mL)
Estradiol 0.037
± 0.048
12.7
± 9.1
0.676
± 0.737
0.030
± 0.032
17.32
± 1.21
0.561
± 0.572
Estrone
Total a
3.68
± 1.55
10.6
± 6.8
61.3
± 26.36
4.93
± 2.07
7.5
± 3.8
85.9
± 41.2
Equilin
Total a
2.27
± 0.95
6.0
± 4.0
28.8
± 13.0
3.22
± 1.13
5.3
± 2.6
38.1
± 20.2


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine Do not exceed 10 mg atorvastatin daily
Clarithromycin, itraconazole, HIV protease inhibitors (ritonavir plus saquinavir or lopinavir plus ritonavir) Caution when exceeding doses > 20 mg atorvastatin daily. The lowest dose necessary should be used.


Table name:
Interacting Agents Prescribing Recommendations
Cyclosporine Do not exceed 10 mg atorvastatin daily
Clarithromycin, itraconazole, HIV protease inhibitors (ritonavir plus saquinavir or lopinavir plus ritonavir) Caution when exceeding doses > 20 mg atorvastatin daily. The lowest dose necessary should be used.


Table name:
Table 2 Steady-State Plasma Concentrations of Felbamate When Coadministered With Other AEDs
AED Coadministered AED Concentration Felbamate Concentration
Phenytoin
Valproate ↔**
Carbamazepine (CBZ)*CBZ epoxide ↓↑
Phenobarbital
*Not significant but an active metabolie of carbamazepine. **No significant effect.


Table name:
CYP2C19 or CYP3A4 Inducers
Clinical Impact: Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology (12.3)].
Intervention: St. John’s Wort, rifampin: Avoid concomitant use with omeprazole [see Warnings and Precautions (5.9)]. Ritonavir-containing products: see prescribing information for specific drugs.
CYP2C19 or CYP3A4 Inhibitors
Clinical Impact: Increased exposure of omeprazole [see Clinical Pharmacology (12.3)].
Intervention: Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered. See prescribing information for voriconazole.


Table name:
Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug Dosing Schedule Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio Change relative to reference) Risperidone Dose Recommendation
Coadministered Drug Risperidone AUC Cmax
Enzyme (CYP2D6) Inhibitors
Fluoxetine 20 mg/day 2 or 3 mg twice daily 1.4 1.5 Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine 10 mg/day 4 mg/day 1.3 - Re-evaluate dosing. Do not exceed 8 mg/day
20 mg/day 4 mg/day 1.6 -
40 mg/day 4 mg/day 1.8 -
Enzyme (CYP3A/PgP inducers) Inducers
Carbamazepine 573 ± 168 mg/day 3 mg twice daily 0.51 0.55 Titrate dose upwards. Do not exceed twice the patient's usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine 150 mg twice daily 1 mg single dose 1.2 1.4 Dose adjustment not needed
Cimetidine 400 mg twice daily 1 mg single dose 1.1 1.3 Dose adjustment not needed
Erythromycin 500 mg four times daily 1 mg single dose 1.1 0.94 Dose adjustment not needed
Other Drugs
Amitriptyline 50 mg twice daily 3 mg twice daily 1.2 1.1 Dose adjustment not needed


Table name:
Drugs That Interfere with Hemostasis
Clinical Impact: • Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of VOLTAREN ® GEL with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions ( 5.11)].
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions ( 5.2)].
Intervention: Concomitant use of VOLTAREN ® GEL and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions ( 5.11)]. VOLTAREN ® GEL is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: • During concomitant use of VOLTAREN ® GEL and ACE-inhibitors, ARBs, or beta- blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of VOLTAREN ® GEL and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions ( 5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter .
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of VOLTAREN ® GEL with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ see Warnings and Precautions ( 5.6)].
Digoxin
Clinical Impact: The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of VOLTAREN ® GEL and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of VOLTAREN ® GEL and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of VOLTAREN ® GEL and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of VOLTAREN ® GEL and cyclosporine may increase cyclosporine's nephrotoxicity.
Intervention: During concomitant use of VOLTAREN ® GEL and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions ( 5.2)].
Intervention: The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of VOLTAREN ® GEL and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of VOLTAREN ® GEL and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and Gl toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.


Table name:
Concomitant Drug Class or  Food Noted or Anticipated Outcome Clinical Comment
HMG-Co A Reductase
Inhibitors:

atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin
Pharmacokinetic and/or pharmacodynamic
interaction: the addition of one drug to a  stable long-term regimen of the other has  resulted in myopathy and rhabdomyolysis (including a fatality)
Weigh the potential benefits and risks and
carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during initial
therapy; monitoring CPK (creatine
phosphokinase) will not necessarily prevent  the occurrence of severe myopathy.
Other Lipid-Lowering Drugs:
fibrates, gemfibrozil
Digitalis Glycosides:
digoxin
P-gp substrate; rhabdomyolysis has been
reported


Table name:
AED Coadministered AED Concentration Topiramate Concentration
Phenytoin NC or 25% increase= Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. 48% decrease
Carbamazepine (CBZ) NC 40% decrease
CBZ epoxide= Is not administered but is an active metabolite of carbamazepine. NC NE
Valproic acid 11% decrease 14% decrease
Phenobarbital NC NE
Primidone NC NE
Lamotrigine NC at TPM doses up to 400 mg/day 13% decrease


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
↓ = Decreased (induces lamotrigine glucuronidation).
↑ = Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
Concomitant Drug 
Effect on Concentration of 
Lamotrigine or Concomitant Drug 
Clinical Comment 
Estrogen-containing oral 
contraceptive 
preparations containing 30 mcg 
ethinylestradiol and 150 mcg levonorgestrel 
↓ lamotrigine 

↓ levonorgestrel 
Decreased lamotrigine concentrations approximately 50%. 

Decrease in levonorgestrel component by 19%. 
Carbamazepine and carbamazepine epoxide 
↓ lamotrigine 


? carbamazepine epoxide 
Addition of carbamazepine decreases 
lamotrigine concentration approximately 40%. 
May increase carbamazepine epoxide levels. 
Lopinavir/ritonavir 
↓ lamotrigine 
Decreased lamotrigine concentration approximately 50%. 
Atazanavir/ritonavir 
↓ lamotrigine
Decreased lamotrigine AUC approximately 32%. 
Phenobarbital/Primidone 
↓ lamotrigine 
Decreased lamotrigine concentration
 approximately 40%. 
Phenytoin 
↓ lamotrigine 
Decreased lamotrigine concentration 
approximately 40%. 
Rifampin 
↓ lamotrigine 
Decreased lamotrigine AUC 
approximately 40%. 
Valproate 
↑ lamotrigine

 ? valproate 
Increased lamotrigine concentrations 
slightly more than 2-fold. 
There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.


Table name:
Drugs that Affect Renal Function A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDS], COX-2 inhibitors may impair the excretion of digoxin.
Antiarrthymics Dofetilide Concomitant administration with digoxin was associated with a higher rate of torsades de pointes
Sotalol Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
Dronedarone Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone Analog Teriparatide Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement Thyroid Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics Epinephrine
Norepinephrine     
Dopamine
Can increase the risk of cardiac arrhythmias
Neuromuscular Blocking Agents      Succinylcholine May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.
Supplements Calcium If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.


Table name:
See Table 3 for clinically significant drug interactions with celecoxib. Table 3: Clinically Significant Drug Interactions with Celecoxib EndCaption
Drugs That Interfere with Hemostasis
Clinical Impact:
   Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of Celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.
   Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:
Monitor patients with concomitant use of celecoxib with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11) ].
Aspirin
Clinical Impact:
Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2) ].
In two studies in healthy volunteers, and in patients with osteoarthritis and established heart disease respectively, celecoxib (200 to 400 mg daily) has demonstrated a lack of interference with the cardioprotective antiplatelet effect of aspirin (100 to 325 mg).


Intervention:
Concomitant use of celecoxib and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11) ].
Celecoxib is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers



Clinical Impact:

       NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).
       In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.




Intervention:

        During concomitant use of celecoxib and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.
       During concomitant use of celecoxib and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6) ].
       When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics


Clinical Impact:

Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.

Intervention:

During concomitant use of celecoxib with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6) ].
Digoxin

Clinical Impact:

The concomitant use of celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:

During concomitant use of celecoxib and digoxin, monitor serum digoxin levels.
Lithium


Clinical Impact:

NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:
During concomitant use of celecoxib and lithium, monitor patients for signs of lithium toxicity.
Methotrexate


Clinical Impact:

Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Celecoxib has no effect on methotrexate pharmacokinetics.
Intervention:
During concomitant use of celecoxib and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:

Concomitant use of celecoxib and cyclosporine may increase cyclosporine's nephrotoxicity.
Intervention:
During concomitant use of celecoxib and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates

Clinical Impact:

Concomitant use of celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2) ].
Intervention:
The concomitant use of celecoxib with other NSAIDs or salicylates is not recommended.
Pemetrexed

Clinical Impact:

Concomitant use of celecoxib and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).




Intervention:
During concomitant use of celecoxib and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.
NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.
In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
CYP2C9 Inhibitors or inducers
Clinical Impact:

Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Co-administration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of celecoxib.
Intervention:
Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers. [see Clinical Pharmacology (12.3) ].
CYP2D6 substrates
Clinical Impact:

In vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6 (e.g. atomoxetine), and celecoxib may enhance the exposure and toxicity of these drugs.
Intervention:
Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2D6 substrates. [see Clinical Pharmacology (12.3) ].
Corticosteroids
Clinical Impact:

Concomitant use of corticosteroids with celecoxib may increase the risk of GI ulceration or bleeding.
Intervention:
Monitor patients with concomitant use of celecoxib with corticosteroids for signs of bleeding [see Warnings and Precautions (5.2)].


Table name:
Table 7 Summary of AED Interactions with Oxcarbazepine Tablets, USP
AED Coadministered Dose of AED
(mg/day)
Oxcarbazepine Tablets Dose
(mg/day)
Influence of Oxcarbazepine Tablets on AED Concentration
(Mean Change, 90% Confidence Interval)
Influence of AED on MHD Concentration
(Mean Change, 90% Confidence Interval)
Carbamazepine 400-2000 900 ncnc denotes a mean change of less than 10% 40% decrease
[CI: 17% decrease, 57% decrease]
Phenobarbital 100-150 600-1800 14% increase
[CI: 2% increase, 24% increase]
25% decrease
[CI: 12% decrease, 51% decrease]
Phenytoin 250-500 600-1800
>1200-2400
nc , Pediatrics up to 40% increaseMean increase in adults at high oxcarbazepine tablets, USP doses
[CI: 12% increase, 60% increase]
30% decrease
[CI: 3% decrease, 48% decrease]
Valproic acid 400-2800 600-1800 nc 18% decrease
[CI: 13% decrease, 40% decrease]


Table name:
Table 3 Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or on Predicted Interaction with INVIRASE/ritonavir
Concomitant Drug Class:
Drug Name
Effect on Concentration of Saquinavir or Concomitant Drug Clinical Comment
HIV-1 Antiviral Agents
Non-nucleoside reverse transcriptase inhibitor:
DelavirdineINVIRASE/ritonavir interaction has not been evaluated.
↑ Saquinavir

Effect on delavirdine is not well established
Appropriate doses of the combination with respect to safety and efficacy have not been established. Coadministration is not recommended.
Liver function should be monitored frequently if this combination is prescribed.
Non-nucleoside reverse transcriptase inhibitor:
EfavirenzSee Pharmacokinetics, Drug Interactions (12.3), Table 6 and Table 7 for magnitude of interactions.,
nevirapine
↓ Saquinavir
↔ Efavirenz


Appropriate doses of the combination of efavirenz or nevirapine and INVIRASE/ritonavir with respect to safety and efficacy have not been established. Coadministration is not recommended.
HIV-1 protease inhibitor:
Indinavir
↑ Saquinavir
↑ Indinavir
Appropriate doses of the combination of indinavir and INVIRASE/ritonavir with respect to safety and efficacy have not been established. Coadministration is not recommended.
Increased concentrations of indinavir may result in nephrolithiasis. For further details see complete prescribing information for Crixivan® (indinavir).
HIV-1 protease inhibitor:
Lopinavir/ritonavir (coformulated tablet)
↔ Saquinavir
↔ Lopinavir
↓ Ritonavir
Evidence from several clinical trials indicates that saquinavir concentrations achieved with the saquinavir and lopinavir/ritonavir combination are similar to those achieved following INVIRASE/ritonavir 1000/100 mg. The recommended dose for this combination is INVIRASE 1000 mg plus lopinavir/ritonavir 400/100 mg bid.

Lopinavir/ritonavir in combination with INVIRASE should be used with caution. Additive effects on QT and/or PR interval prolongation may occur with INVIRASE [see Warnings and Precautions (5.2, 5.3)].
HIV-1 protease inhibitor:
Nelfinavir
↑ Saquinavir
Combining saquinavir/ritonavir with nelfinavir is not recommended.
HIV-1 protease inhibitor:
Tipranavir/ritonavir
↓ Saquinavir
Combining saquinavir with tipranavir/ritonavir is not recommended.
HIV-1 CCR5 antagonist:
Maraviroc
↑ Maraviroc Maraviroc dose should be 150 mg twice daily when coadministered with INVIRASE/ritonavir. For further details see complete prescribing information for Selzentry® (maraviroc).
Other Agents
Ibutilide
Sotalol
Additive effects on QT and/or PR interval prolongation may occur with INVIRASE/ritonavir [see Contraindications (4) and Warnings and Precautions (5.2, 5.3)]. Coadministration of INVIRASE/ritonavir and ibutilide or sotalol is not recommended.
Anticoagulant:
Warfarin
↑ Warfarin Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants:
Carbamazepine, phenobarbital, phenytoin
↓ Saquinavir

Effect on carbamazepine, phenobarbital, and phenytoin is not well established
Saquinavir may be less effective due to decreased saquinavir plasma concentrations in patients taking these agents concomitantly. Coadministration is not recommended.
Anti-gout:
Colchicine
↑ Colchicine Treatment of gout flares-coadministration of colchicine in patients on INVIRASE/ritonavir:

0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days.

Treatment of familial Mediterranean fever (FMF) coadministration of colchicine in patients on INVIRASE/ritonavir:

Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).

Prophylaxis of gout-flares-co-administration of colchicine in patients on INVIRASE/ritonavir:

If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.

If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.

Patients with renal or hepatic impairment should not be given colchicine with INVIRASE/ritonavir.
Streptogramin antibiotics (quinupristin/dalfopristin) Streptogramin antibiotics such as quinupristin/dalfopristin inhibit CYP3A4; saquinavir concentrations may be increased Monitoring for saquinavir toxicity is recommended. Use with caution due to possible cardiac arrhythmias.
Fusidic acid ↑ Saquinavir
↑ Fusidic Acid
↑ Ritonavir
Concomitant use of fusidic acid and INVIRASE/ritonavir is not recommended due to potential for increased mutual toxicities.
 
The interaction between INVIRASE/ritonavir and fusidic acid has not been formally evaluated. Co-administration of fusidic acid and INVIRASE/ritonavir can cause increased plasma concentrations of fusidic acid, saquinavir and ritonavir.
Antifungal:
Ketoconazole,
itraconazole
↔ Saquinavir
↔ Ritonavir
↑ Ketoconazole
When INVIRASE/ritonavir and ketoconazole are coadministered, plasma concentrations of ketoconazole are increased (see Table 6 ). Hence, doses of ketoconazole or itraconazole >200 mg/day are not recommended.
Antimycobacterial:
Rifabutin
↔ Saquinavir
↑ Rifabutin
↔ Ritonavir

No dose adjustment of INVIRASE/ritonavir (1000/100 mg bid) is required if INVIRASE/ritonavir is administered in combination with rifabutin.

Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse events including neutropenia and liver enzyme levels is warranted in patients receiving the combination.

Consider monitoring rifabutin concentrations to ensure adequate exposure.
Antipsychotic:
Quetiapine
↑ Quetiapine Initiation of INVIRASE with ritonavir in patients taking quetiapine:
Consider alternative antiretroviral therapy to avoid increases in quetiapine drug exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring.

Initiation of quetiapine in patients taking INVIRASE with ritonavir:
Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.
Benzodiazepines :
Alprazolam, clorazepate, diazepam, flurazepam
↑ Benzodiazepines Clinical significance is unknown. Careful monitoring of patients for benzodiazepine effects is warranted; a decrease in benzodiazepine dose may be needed.
Benzodiazepine :
Intravenously administered Midazolam
↑ Midazolam If INVIRASE/ritonavir is coadministered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.
Calcium channel blockers :
Diltiazem, felodipine, nifedipine, nicardipine, nimodipine, verapamil, amlodipine, nisoldipine, isradipine
↑ Calcium channel blockers Caution is warranted and clinical monitoring of patients is recommended.
Corticosteroid:
Dexamethasone
↓ Saquinavir
INVIRASE/ritonavir may be less effective due to decreased saquinavir plasma concentrations. Coadministration is not recommended.
Digitalis Glycosides: Digoxin ↑ Digoxin

Increases in serum digoxin concentration were greater in female subjects as compared to male subjects when digoxin was coadministered with INVIRASE/ritonavir.
Caution should be exercised when INVIRASE/ritonavir and digoxin are coadministered; serum digoxin concentrations should be monitored and the dose of digoxin may need to be reduced when coadministered with INVIRASE/ritonavir.
Endothelin receptor antagonists:
Bosentan
↑ Bosentan Coadministration of bosentan in patients on INVIRASE/ritonavir:

In patients who have been receiving INVIRASE/ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

Coadministration of INVIRASE/ritonavir in patients on bosentan:

Discontinue use of bosentan at least 36 hours prior to initiation of INVIRASE/ritonavir.

After at least 10 days following the initiation of INVIRASE/ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Inhaled beta agonist:
Salmeterol
↑ Salmeterol Concurrent administration of salmeterol with INVIRASE/ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Inhaled/nasal steroids:
Fluticasone
Budesonide
↑ Fluticasone Concomitant use of fluticasone propionate and INVIRASE/ritonavir may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Several cases of Cushing's disease associated with this interaction have been reported in the literature. Coadministration of fluticasone propionate and INVIRASE/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects. If the combination is nevertheless considered necessary, a dose reduction of fluticasone propionate with close monitoring of local and systemic effects is recommended.
A switch to a corticosteroid which is not a substrate for CYP3A (e.g., beclomethasone) should be considered. In case of withdrawal of corticosteroids, progressive dose reduction may have to be performed over a longer period.
HMG-CoA reductase inhibitors :
Atorvastatin
↑ Atorvastatin
Titrate atorvastatin dose carefully and use the lowest dose necessary; do not exceed atorvastatin 20 mg/day. Patients should be carefully monitored for signs and symptoms of myopathy (e.g., muscle weakness, muscle pain, rising creatine kinase).
Immunosuppressants :
Cyclosporine, rapamycin
↑ Immunosuppressants Therapeutic concentration monitoring is recommended for immunosuppressant agents when coadministered with INVIRASE/ritonavir.
Narcotic analgesic:
Methadone
↓ Methadone Dosage of methadone may need to be increased when coadministered with INVIRASE/ritonavir.

Use with caution. Additive effects on QT and/or PR interval prolongation may occur with INVIRASE/ritonavir [see Contraindications (4) and Warnings and Precautions (5.2, 5.3)].
Oral contraceptives:
Ethinyl estradiol
↓ Ethinyl estradiol Alternative or additional contraceptive measures should be used when estrogen-based oral contraceptives and INVIRASE/ritonavir are coadministered.
PDE5 inhibitors (phosphodiesterase type 5 inhibitors):
Sildenafil, vardenafil, tadalafil
↑ Sildenafil
↔ Saquinavir

↑ Vardenafil
↑ Tadalafil

Only the combination of sildenafil with saquinavir soft gelatin capsules has been studied at doses used for treatment of erectile dysfunction.
May result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism.

Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH): Use of sildenafil (Revatio) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) [see Contraindications (4)]. The following dose adjustments are recommended for use of tadalafil (Adcirca®) with INVIRASE/ritonavir:

Coadministration of Adcirca in patients on INVIRASE/ritonavir:

In patients receiving INVIRASE/ritonavir for at least one week, start Adcirca at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Coadministration of INVIRASE/ritonavir in patients on Adcirca:

Avoid use of Adcirca during the initiation of INVIRASE/ritonavir. Stop Adcirca at least 24 hours prior to starting INVIRASE/ritonavir. After at least one week following the initiation of INVIRASE/ritonavir, resume Adcirca at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Use of PDE5 inhibitors for erectile dysfunction:

Use sildenafil with caution at reduced doses of 25 mg every 48 hours with increased monitoring of adverse events when administered concomitantly with INVIRASE/ritonavir.

Use vardenafil with caution at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring of adverse events when administered concomitantly with INVIRASE/ritonavir.

Use tadalafil with caution at reduced doses of no more than 10 mg every 72 hours with increased monitoring of adverse events when administered concomitantly with INVIRASE/ritonavir.
Tricyclic antidepressants : Amitriptyline, clomipramine, imipramine, maprotiline ↑ Tricyclics Therapeutic concentration monitoring is recommended for tricyclic antidepressants when coadministered with INVIRASE/ritonavir.
Other antidepressants:
Nefazodone
↑ Saquinavir Monitoring for saquinavir toxicity is recommended.
Proton pump inhibitors: Omeprazole ↑ Saquinavir When INVIRASE/ritonavir is co-administered with omeprazole, saquinavir concentrations are increased significantly. If omeprazole or another proton pump inhibitor is taken concomitantly with INVIRASE/ritonavir, caution is advised and monitoring for potential saquinavir toxicities is recommended, particularly gastrointestinal symptoms, increased triglycerides, deep vein thrombosis, and QT prolongation.
Herbal Products:
St. John's wort (hypericum perforatum)
↓ Saquinavir Herbal products containing St. John's wort should not be used concomitantly with INVIRASE/ritonavir because coadministration may lead to loss of virologic response and possible resistance to INVIRASE or to the class of protease inhibitors.
Other drugs that are substrates of CYP3A:
Fentanyl
Alfentanil
↑ Fentanyl
↑ Alfentanil
Coadministration with these drugs may accentuate the side effects reported with use of fentanyl or alfentanil including respiratory depression, apnea and bradycardia.
Vasodilators (peripheral):
Intravenously administered Vincamine
↑ Vincamine Monitoring for vincamine toxicity is recommended. Use with caution due to potential cardiac arrhythmias.
Garlic Capsules ↓ Saquinavir Coadministration of garlic capsules and saquinavir is not recommended due to the potential for garlic capsules to induce the metabolism of saquinavir which may result in sub-therapeutic saquinavir concentrations.


Table name:
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Do not exceed 40 mg atorvastatin daily


Table name:
Table 2: Drug-Thyroidal Axis Interactions
 Drug or Drug Class  Effect
 Drugs that may reduce TSH secretion–the reduction is not sustained; therefore, hypothyroidism does not occur
 Dopamine / Dopamine Agonists
Glucocorticoids
Octreotide
 Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day).
 Drugs that alter thyroid hormone secretion
 Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
 Aminoglutethimide
Amiodarone
Iodide(including iodine-containing
  Radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
 Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients.  The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
 Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
 Amiodarone
Iodide(including iodine-containing   
  Radiographic contrast agents)
 Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma).  Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
 Drugs that may decrease T 4 absorption, which may result in hypothyroidism
 Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
 Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism.  Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents.  Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
 Drugs that may alter T 4 and T 3 serum transport  - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
 Drugs that may increase serum TBG concentration  Drugs that may decrease serum TBG concentration
 Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
 Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
 Drugs that may cause protein-binding site displacement
 Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
 Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4, and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
 Drugs that may alter T 4 and T 3 metabolism
 Drugs that may increase hepatic metabolism, which may result  in hypothyroidism
 Carbamazepine
Hydantoins
Phenobarbital
Rifampin
 Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
 Drugs that may decrease T 4 5’-deiodinase activity
 Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
 Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4  levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
 Miscellaneous
 Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
 Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
 Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors
  (SSRIs; e.g., Sertraline)
 Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of  tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
 Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
 Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
 Cardiac Glycosides  Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
 Cytokines
- Interferon-α
- Interleukin-2
 Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
 Growth Hormones
- Somatrem
- Somatropin
 Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
 Ketamine  Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
 Methylxanthine Bronchodilators
- (e.g., Theophylline)
 Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
 Radiographic Agents  Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
 Sympathomimetics  Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
 Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
 These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.


Table name:
blood dyscrasias -
seeCONTRAINDICATIONS
cancer
collagen vascular disease
congestive heart failure
diarrhea
elevated temperature
hepatic disorders
infectious hepatitis
jaundice
hyperthyroidism
poor nutritional state
steatorrhea
vitamin K deficiency


Table name:
Drugs/Dietary Supplements That Decrease Cyclosporine Concentrations
Antibiotics nafcillin rifampin Anticonvulsants carbamazepine oxcarbazepine phenobarbital phenytoin Other Drugs / Dietary Supplements bosentan octreotide orlistat St. John’s Wort sulfinpyrazone terbinafine ticlopidine 


Table name:
Inhibitors of CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6
Clinical Impact: Methadone undergoes hepatic N-demethylation by several cytochrome P450 (CYP) isoforms, including CYP3A4, CYP2B6, CYP2C19, CYP2C9, and CYP2D6. The concomitant use of methadone hydrochloride tablets and CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitors can increase the plasma concentration of methadone, resulting in increased or prolonged opioid effects, and may result in a fatal overdose, particularly when an inhibitor is added after a stable dose of methadone hydrochloride tablets is achieved. These effects may be more pronounced with concomitant use of drugs that inhibit more than one of the CYP enzymes listed above. After stopping a CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitor, as the effects of the inhibitor decline, the methadone plasma concentration can decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy or withdrawal symptoms in patients physically dependent on methadone.
Intervention: If concomitant use is necessary, consider dosage reduction of methadone hydrochloride tablets until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitor is discontinued, follow patients for signs of opioid withdrawal and consider increasing the methadone hydrochloride tablets dosage until stable drug effects are achieved.
Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir), fluconazole, fluvoxamine, some selective serotonin reuptake inhibitors (SSRIs) (e.g., sertraline, fluvoxamine)
Inducers of CYP3A4, CYP2B6, CYP2C19, or CYP2C9
Clinical Impact: The concomitant use of methadone hydrochloride tablets and CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers can decrease the plasma concentration of methadone [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of withdrawal symptoms in patients physically dependent on methadone. These effects could be more pronounced with concomitant use of drugs that can induce multiple CYP enzymes. After stopping a CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducer, as the effects of the inducer decline, the methadone plasma concentration can increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression, sedation, or death.
Intervention: If concomitant use is necessary, consider increasing the methadone hydrochloride tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducer is discontinued, consider methadone hydrochloride tablets dosage reduction and monitor for signs of respiratory depression and sedation.
Examples: Rifampin, carbamazepine, phenytoin, St. John’s Wort, Phenobarbital
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death.
Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.6)].
Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Potentially Arrhythmogenic Agents
Clinical Impact: Pharmacodynamic interactions may occur with concomitant use of methadone and potentially arrhythmogenic agents or drugs capable of inducing electrolyte disturbances (hypomagnesemia, hypokalemia).
Intervention: Monitor patients closely for cardiac conduction changes.
Examples: Drugs known to have potential to prolong QT interval: Class I and III antiarrhythmics, some neuroleptics and tricyclic antidepressants, and calcium channel blockers. Drugs capable of inducing electrolyte disturbances: Diuretics, laxatives, and, in rare cases, mineralocortocoid hormones.
Serotonergic Drugs
Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Warnings and Precautions (5.8)].
Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue methadone hydrochloride tablets if serotonin syndrome is suspected.
Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome [see Warnings and Precautions (5.8)] or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)].
Intervention: The use of methadone hydrochloride tablets is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact: May reduce the analgesic effect of methadone hydrochloride tablets and/or precipitate withdrawal symptoms.
Intervention: Avoid concomitant use.
Examples: butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact: Methadone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of methadone hydrochloride tablets and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when methadone hydrochloride tablets are used concomitantly with anticholinergic drugs.


Table name:
Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s)
Recommendation
Comments
Tizanidine
Contraindicated
Concomitant administration of tizanidine and ciprofloxacin  is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2) ].
Theophylline
Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)
Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate. [See Warnings and Precautions (5.9) .]
Drugs Known to Prolong QT Interval
Avoid Use
 
Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see  Warnings and Precautions (5.11) and Use in   Specific Populations (8.5) ].
Oral antidiabetic drugs
Use with caution Glucose-lowering effect potentiated
Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs. [See Adverse Reactions (6.1) .]
Phenytoin
Use with caution Altered serum levels of phenytoin
(increased and decreased)
 
To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin with phenytoin.
Cyclosporine
Use with caution (transient elevations in serum creatinine)
Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs
Use with caution (Increase in anticoagulant effect)
The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate
Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels
Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole
Use with caution
Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin [see Warnings and Precautions (5.16) ].
Clozapine
Use with caution
Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs
Use with caution
Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies in and postmarketing.
Sildenafil
Use with caution Two-fold increase in exposure
Monitor for sildenafil toxicity (see Clinical Pharmacology (12.3 )].
Duloxetine
Avoid Use
Five-fold increase in duloxetine exposure
If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives
Use with caution Reduced clearance resulting in elevated levels and prolongation
of serum half-life
Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx® (didanosine) chewable/ buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)
Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2.4)] .
Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid
Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)
Potentiation of ciprofloxacin toxicity may occur.


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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C Protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


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Figure 1: Effect of interacting drugs on the pharmacokinetics of venlafaxine and active metabolite O-desmethylvenlafaxine (ODV).


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I. Due to the competition of salicylate with other drugs for binding to serum albumin the following drug interactions may occur:
DRUG DESCRIPTION OF INTERACTION
Sulfonylureas Hypoglycemia potentiated.
Methotrexate Decreases tubular reabsorption; clinical toxicity from methotrexate can result.
Oral Anticoagulants Increased bleeding.
II. Drugs changing salicylate levels by altering renal tubular reabsorption:
DRUG DESCRIPTION OF INTERACTION
Corticosteroids Decreases plasma salicylate level; tapering doses of steroids may promote salicylism.
Acidifying Agents Increases plasma salicylate levels.
Alkanizing Agents Decreased plasma salicylate levels.
III. Drugs with complicated interactions with salicylates:
DRUG DESCRIPTION OF INTERACTION
Heparin Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients.
Pyrazinamide Inhibits pyrazinamide-induced hyperuricemia.
Uricosuric Agents Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited.
The following alterations of laboratory tests have been reported during salicylate therapy:
LABORATORY TESTS EFFECT OF SALICYLATES
Thyroid Function Decreased PBI; increased t3 uptake.
Urinary Sugar False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5g q.d.).
5-Hydroxyindole acetic acid False negative with fluorometric test.
Acetone ketone bodies False positive FeCI3 in Gerhardt reaction; red color persists with boiling.
17-OH corticosteroids False reduced values with >4.8g q.d. salicylate.
Vanilmandelic acid False reduced values.
Uric Acid May increase or decrease depending on dose.
Prothrombin Decreased levels; slightly increased prothrombin time.


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Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) VIAGRA 50 mg (95% CI)
Supine 9.08 (5.48, 12.68)
Standing

11.62 (7.34, 15.90)



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Drugs That Interfere with Hemostasis
Clinical Impact: • Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of naproxen or naproxen sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: Concomitant use of naproxen or naproxen sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen or naproxen sodium is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE-inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: • During concomitant use of naproxen or naproxen sodium and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of naproxen or naproxen sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen or naproxen sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact: The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of naproxen or naproxen sodium and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen or naproxen sodium and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of naproxen or naproxen sodium and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of naproxen or naproxen sodium and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of naproxen or naproxen sodium and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of naproxen or naproxen sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of naproxen or naproxen sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact: Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention: Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen or naproxen sodium is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed release tablets are not recommended.
Cholestyramine
Clinical Impact: Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention: Concomitant administration of cholestyramine with naproxen or naproxen sodium is not recommended.
Probenecid
Clinical Impact: Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention: Patients simultaneously receiving naproxen or naproxen sodium and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact: Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention: Patients simultaneously receiving naproxen or naproxen sodium and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.


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Table 3. Clinically Significant Drug Interactions Involving Drugs that Affect Cabozantinib
   Strong CYP3A4 Inhibitors
Clinical Implications:   Concomitant use of CABOMETYX with a strong CYP3A4 inhibitor increased the exposure of cabozantinib compared to the use of CABOMETYX alone [see Clinical Pharmacology (12.3)]. Increased cabozantinib exposure may increase the risk of exposure-related toxicity.
Prevention or Management:   Reduce the dosage of CABOMETYX if concomitant use with strong CYP3A4 inhibitors cannot be avoided [see Dosage and Administration (2.2)].
Examples:   Boceprevir, clarithromycin, conivaptan, grapefruit juiceThe effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation dependent. Studies have shown that it can be classified as a "strong CYP3A inhibitor" when a certain preparation was used (e.g., high dose, double strength) or as a "moderate CYP3A inhibitor" when another preparation was used (e.g., low dose, single strength)., indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telithromycin, and voriconazole
   Strong CYP3A4 Inducers
Clinical Implications:   Concomitant use of CABOMETYX with a strong CYP3A4 inducer decreased the exposure of cabozantinib compared to the use of CABOMETYX alone [see Clinical Pharmacology (12.3)]. Decreased cabozantinib exposure may lead to reduced efficacy.
Prevention or Management:   Increase the dosage of CABOMETYX if concomitant use with strong CYP3A4 inducers cannot be avoided [see Dosage and Administration (2.2)].
Examples:   Rifampin, phenytoin, carbamazepine, phenobarbital, rifabutin, rifapentine, and St. John’s WortThe effect of St. John’s Wort varies widely and is preparation-dependent


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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 7.8, 12.3)
Interacting Agents Prescribing Recommendations
Strong CYP3A4 Inhibitors, (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin,
clarithromycin, telithromycin,
HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol
Contraindicated with VYTORIN
Verapamil, diltiazem, dronedarone Do not exceed 10/10 mg VYTORIN daily
Amiodarone, amlodipine, ranolazine Do not exceed 10/20 mg VYTORIN daily
Lomitapide For patients with HoFH, do not exceed 10/20 mg VYTORIN daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 10/40 mg VYTORIN when taking lomitapide.
Grapefruit juice Avoid grapefruit juice


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Table 5. Established and Other Potentially Significant Drug Interactions
↓= Decreased (induces lamotrigine glucuronidation).
↑= Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine ↓levonorgestrel Decreased lamotrigine concentrations approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine and Carbamazepine epoxide ↓ lamotrigine ? carbamazepine epoxide Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels.
Lopinavir/ritonavir ↓ lamotrigine Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir ↓ lamotrigine Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine ? valproate Increased lamotrigine concentrations slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.


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Table 7 Summary of AED Interactions with Oxcarbazepine Tablets
AED Coadministered Dose of AED (mg/day)
Oxcarbazepine Tablets Dose (mg/day)
Influence of Oxcarbazepine Tablets on AED Concentration (Mean Change, 90% Confidence Interval) Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine 400-2000 900 nc nc denotes a mean change of less than 10% 40% decrease [CI:17% decrease, 57% decrease]
Phenobarbital 100-150 600-1800 14% increase [CI: 2% increase, 24% increase] 25% decrease [CI:12% decrease, 51% decrease]
Phenytoin 250-500 600-1800 nc , Pediatrics 30% decrease
>1200-2400 up to 40% increase [CI: 12% increase, 60% increase] Mean increase in adults at high oxcarbazepine tablets doses [CI: 3% decrease, 48% decrease]
Valproic acid 400-2800 600-1800 nc 18% decrease [CI:13% decrease, 40% decrease]


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Table 18. Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
* Change relative to reference
Coadministered Drug
Dosing Schedule
Effect on Active
Moiety (Risperidone +
9-Hydroxy-
Risperidone Ratio*)
Risperidone
Dose
Recommendation
Coadministered
Drug
Risperidone
AUC
Cmax
Enzyme (CYP2D6)
Inhibitors
 
 
 
 
 
Fluoxetine
20 mg/day
2 or 3 mg twice daily
1.4
1.5
Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine
10 mg/day
4 mg/day
1.3
-
Re-evaluate dosing. Do not exceed 8 mg/day
 
20 mg/day
4 mg/day
1.6
-
 
40 mg/day
4 mg/day
1.8
-
Enzyme (CYP3A/
PgP inducers)
Inducers
 
 
 
 
 
Carbamazepine
573 ± 168 mg/day
3 mg twice daily
0.51
0.55
Titrate dose upwards. Do not exceed twice the patient's usual dose
Enzyme (CYP3A)
Inhibitors
 
 
 
 
 
Ranitidine
150 mg twice daily
1 mg single dose
1.2
1.4
Dose adjustment not needed
Cimetidine
400 mg twice daily
1 mg single dose
1.1
1.3
Dose adjustment not needed
Erythromycin
500 mg four times daily
1 mg single dose
1.1
0.94
Dose adjustment not needed
Other Drugs
 
 
 
 
 
Amitriptyline
50 mg twice daily
3 mg twice daily
1.2
1.1
Dose adjustment not needed


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Interacting Drug Interaction
Multivalent cation- containing products including: antacids, sucralfate, multivitamins Decreased moxifloxacin hydrochloride absorption. Take moxifloxacin hydrochloride tablet at least 4 hours before or 8 hours after these products. ( 2.2, 7.1, 12.3)
Warfarin Anticoagulant effect enhanced. Monitor prothrombin time/INR, and bleeding. ( 6, 7.2, 12.3)
Class IA and Class III antiarrhythmics: Proarrhythmic effect may be enhanced. Avoid concomitant use. ( 5.6, 7.5)
Antidiabetic agents Carefully monitor blood glucose. ( 5.11, 7.3)


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Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Grapefruit juice Avoid grapefruit juice


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Antibiotics Antineoplastics Anti-inflammatory Drugs Gastrointestinal Agents
ciprofloxacin melphalan azapropazon cimetidine
gentamicin   colchicine ranitidine
tobramycin Antifungals diclofenac  
vancomycin amphotericin B naproxen Immunosuppressives
trimethoprim with sulfamethoxazole ketoconazole sulindac tacrolimus
       
      Other Drugs
      fibric acid derivatives
(e.g.,bezafibrate, fenofibrate)
      methotrexate


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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir ) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Do not exceed 40 mg atorvastatin daily


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Figure 2: Effect of venlafaxine on the pharmacokinetics interacting drugs and their active metabolites.


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Drug Interactions Associated with Increased Risk of  Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice Avoid grapefruit juice


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Table 13: Clinically Important Drug Interactions with INVEGA SUSTENNA®
Drugs with Potential for Inducing Orthostatic Hypotension
  Clinical Impact Because INVEGA SUSTENNA® has the potential for inducing orthostatic hypotension, an additive effect may occur when INVEGA SUSTENNA® is administered with other therapeutic agents that have this potential [see Warning and Precautions (5.7)]
  Intervention Monitor orthostatic vital signs in patients who are vulnerable to hypotension [see Warnings and Precautions (5.7)]
  Examples Nitrates
Antihypertensive medicines: thiazide diuretics (e.g. hydrochlorothiazide); beta blockers (e.g. acebutolol); angiotensin-converting enzyme (ACE) inhibitors (e.g. lisinopril); angiotensin II receptor blockers (ARBs) (e.g. candesartan); calcium channel blockers (e.g. amlodipine); alpha-blockers (e.g. prazosin), alpha-agonists (e.g. clonidine), other diuretics (e.g. loop, K-sparing), vasodilators (e.g. hydralazine)
Strong Inducers of CYP3A4 and P-gp
  Clinical Impact The concomitant use of paliperidone and strong inducers of CYP3A4 and P-gp may decrease the exposure of paliperidone [see Clinical Pharmacology (12.3)]
  Intervention Avoid using CYP3A4 and/or P-gp inducers with INVEGA SUSTENNA® during the 1-month dosing interval, if possible. If administering a strong inducer is necessary, consider managing the patient using paliperidone extended release tablets [see Dosage and Administration (2.5)]
  Examples Carbamazepine, rifampin, St John's Wort
Dopamine Agonist
  Clinical Impact Paliperidone may antagonize the effect of levodopa and other dopamine agonist
  Intervention Monitor and manage patient as clinically appropriate
  Examples Levodopa, bromocriptine, ropinirole and pramipexole


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Table 6. Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology (12.3)]
Drug/Drug Class
(Mechanism of Interaction by the Drug)
Voriconazole Plasma Exposure
(Cmax and AUCτ after 200 mg q12h)
Recommendations for Voriconazole Dosage Adjustment/Comments
Rifampin* and Rifabutin*
(CYP450 Induction)
Significantly Reduced Contraindicated
Efavirenz (400 mg q 24h)**
(CYP450 Induction)
Efavirenz (300 mg q 24h) ** (CYP450 Induction)
Significantly Reduced Slight decrease in AUCt Contraindicated When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)** (CYP450 Induction) Significantly Reduced Contraindicated
Low-dose Ritonavir (100 mg q12h)** (CYP450 Induction) Reduced Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Carbamazepine
(CYP450 Induction)
Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction Contraindicated
Long Acting Barbiturates
(CYP450 Induction)
Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction Contraindicated
Phenytoin*
(CYP450 Induction)
Significantly Reduced Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg)
St. John’s Wort
(CYP450 inducer; P-gp inducer)
Significantly Reduced Contraindicated
Oral Contraceptives**
containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)
Increased Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole** (CYP2C9, CYP2C19 and CYP3A4 Inhibition) Significantly Increased Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole.
Other HIV Protease Inhibitors
(CYP3A4 Inhibition)
In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure
In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)
No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIs*** (CYP3A4 Inhibition or CYP450 Induction) In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to voriconazole
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure) Careful assessment of voriconazole effectiveness


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Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s) Recommendation Comments
Tizanidine Contraindicated Concomitant administration of tizanidine and Ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [ see Contraindications ( 4.2) ]
Theophylline Avoid Use (Plasma Exposure Likely to be Increased and Prolonged) Concurrent administration of Ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate. [See Warnings and Precautions ( 5.6).]
Drugs Known to Prolong QT Interval Avoid Use Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions ( 5.10) and Use in Specific Populations ( 8.5)].
Oral antidiabetic drugs
Use with caution Glucose-lowering effect potentiated Hypoglycemia sometimes severe has been reported when Ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when Ciprofloxacin is co-administered with oral antidiabetic drugs. [See Adverse Reactions ( 6.1).]
Phenytoin
Use with caution Altered serum levels of phenytoin (increased and decreased) To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon Ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of Ciprofloxacin with phenytoin.
Cyclosporine
Use with caution (transient elevations in serum creatinine) Monitor renal function (in particular serum creatinine) when Ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs
Use with caution (Increase in anticoagulant effect) The risk may vary with the underlying infection, age and general status of the patient so that the contribution of Ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of Ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate
Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant Ciprofloxacin therapy is indicated.
Ropinirole
Use with caution
Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after coadministration with Ciprofloxacin [see Warnings and Precautions ( 5.15)].
Clozapine
Use with caution
Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with Ciprofloxacin are advised.
NSAIDs
Use with caution
Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil
Use with caution Two-fold increase in exposure Monitor for sildenafil toxicity ( see Pharmacokinetics 12.3 ).
Duloxetine
Avoid Use
Five-fold increase in duloxetine exposure
If unavoidable, monitor for duloxetine toxicity.
Caffeine/Xanthine
Derivatives
Use with caution
Reduced clearance resulting in elevated levels and prolongation of serum half-life
Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx®
(didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)
Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration. ( 2)].
Decrease Ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid Use with caution (interferes with renal tubular secretion of Ciprofloxacin and increases Ciprofloxacin serum levels) Potentiation of Ciprofloxacin toxicity may occur.


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Interaction Drug Interaction
Rifabutin, phenytoin, efavirenz, cimetidine, esomeprazoleThe drug interactions with esomeprazole and metoclopramide do not apply to posaconazole tablets. Avoid coadministration unless the benefit outweighs the risks (7.6, 7.7, 7.8, 7.9)
Other drugs metabolized by CYP3A4 Consider dosage adjustment and monitor for adverse effects and toxicity (7.1, 7.10, 7.11)
Digoxin Monitor digoxin plasma concentrations (7.12)
Fosamprenavir, metoclopramide Monitor for breakthrough fungal infections (7.6, 7.13)


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine Decreased lamotrigine concentrations approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? carbamazepine epoxide May increase carbamazepine epoxide levels.
Lopinavir/ritonavir ↓ lamotrigine Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir ↓ lamotrigine Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine Increased lamotrigine concentrations slightly more than 2 fold.
? valproate There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.


Table name:
Table 5 Effects on steady-state fexofenadine pharmacokinetics after 7 days of co-administration with fexofenadine hydrochloride 120 mg every 12 hours in healthy adult subjects (n=24)
Concomitant Drug CmaxSS
(Peak plasma concentration)
AUCss(0-12h)
(Extent of systemic exposure)
 Erythromycin
(500 mg every 8 hrs)
 +82%  +109%
 Ketoconazole
(400 mg once daily)
 +135%  +164%


Table name:
Table 3. Drugs That May Alter T4 and Triiodothyronine (T3) Serum Transport Without Affecting Free Thyroxine (FT4) Concentration (Euthyroidism)
Drug or Drug Class Effect
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
These drugs may increase serum thyroxine-binding globulin (TBG) concentration.
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
These drugs may decrease serum TBG concentration.
Potential impact (below): Administration of these agents with SYNTHROID results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations.
Salicylates (> 2 g/day) Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total T4 levels may decrease by as much as 30%.
Other drugs:
Carbamazepine
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non-Steroidal Anti-inflammatory Drugs
- Fenamates
These drugs may cause protein-binding site displacement. Furosemide has been shown to inhibit the protein binding of T4 to TBG and albumin, causing an increase free T4 fraction in serum. Furosemide competes for T4-binding sites on TBG, prealbumin, and albumin, so that a single high dose can acutely lower the total T4 level. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total and free T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. Closely monitor thyroid hormone parameters.


Table name:
Table 3: Drug Interactions: Pharmacokinetic Parameters for Coadministered Drug in the Presence of Indinavir (See PRECAUTIONS, Table 9 for Recommended Alterations in Dose or Regimen)
Coadministered drug Dose of Coadministered drug (mg) Dose of CRIXIVAN (mg) n Ratio (with/without CRIXIVAN) of Coadministered Drug
Pharmacokinetic Parameters
(90% CI); No Effect = 1.00
Cmax AUC Cmin
All interaction studies conducted in healthy, HIV-negative adult subjects, unless otherwise indicated.
Clarithromycin 500 twice daily,
7 days
800 three times daily, 7 days 12 1.19
(1.02, 1.39)
1.47
(1.30, 1.65)
1.97
(1.58, 2.46)
n=11
Efavirenz 200 once daily,
14 days
800 three times daily, 14 days 20 No significant change No significant change --
Ethinyl Estradiol
(ORTHO-NOVUM 1/35)Registered trademark of Ortho Pharmaceutical Corporation
35 mcg, 8 days 800 three times daily, 8 days 18 1.02
(0.96, 1.09)
1.22
(1.15, 1.30)
1.37
(1.24, 1.51)
Isoniazid 300 once daily in the morning,
8 days
800 three times daily, 8 days 11 1.34
(1.12, 1.60)
1.12
(1.03, 1.22)
1.00
(0.92, 1.08)
MethadoneStudy conducted in subjects on methadone maintenance. 20-60 once daily in the morning,
8 days
800 three times daily, 8 days 12 0.93
(0.84, 1.03)
0.96
(0.86, 1.06)
1.06
(0.94, 1.19)
Norethindrone
(ORTHO-NOVUM 1/35)
1 mcg, 8 days 800 three times daily, 8 days 18 1.05
(0.95, 1.16)
1.26
(1.20, 1.31)
1.44
(1.32, 1.57)
Rifabutin
150 mg once daily in the morning, 11 days + indinavir compared to 300 mg once daily in the morning, 11 days alone
150 once daily in the morning,
10 days

300 once daily in the morning,
10 days
800 three times daily, 10 days


800 three times daily, 10 days
14



10
1.29
(1.05, 1.59)


2.34
(1.64, 3.35)
1.54
(1.33, 1.79)


2.73
(1.99, 3.77)
1.99
(1.71, 2.31)
n=13

3.44
(2.65, 4.46)
n=9
Ritonavir 100 twice daily,
14 days
800 twice daily,
14 days
10, 4Parallel group design; n for coadministered drug + indinavir, n for coadministered drug alone. 1.61
(1.13, 2.29)
1.72
(1.20, 2.48)
1.62
(0.93, 2.85)
200 twice daily,
14 days
800 twice daily,
14 days
9, 5 1.19
(0.85, 1.66)
1.96
(1.39, 2.76)
4.71
(2.66, 8.33)
n=9, 4
Saquinavir
   Hard gel formulation 600 single dose 800 three times daily, 2 days 6 4.7
(2.7, 8.1)
6.0
(4.0, 9.1)
2.9
(1.7, 4.7)C6hr
   Soft gel formulation 800 single dose 800 three times daily, 2 days 6 6.5
(4.7, 9.1)
7.2
(4.3, 11.9)
5.5
(2.2, 14.1)
   Soft gel formulation 1200 single dose 800 three times daily, 2 days 6 4.0
(2.7, 5.9)
4.6
(3.2, 6.7)
5.5
(3.7, 8.3)
Sildenafil 25 single dose 800 three times daily 6 See text below for discussion of interaction.
StavudineStudy conducted in HIV-positive subjects. 40 twice daily,
7 days
800 three times daily, 7 days 13 0.86
(0.73, 1.03)
1.21
(1.09, 1.33)
Not Done
Theophylline 250 single dose (on Days 1 and 7) 800 three times daily, 6 days (Days 2 to 7) 12, 4 0.88
(0.76, 1.03)
1.14
(1.04, 1.24)
1.13
(0.86, 1.49)
n=7, 3
Trimethoprim/
Sulfamethoxazole
   Trimethoprim 800 Trimethoprim/
160 Sulfamethoxazole q12h, 7 days
400 q6h, 7 days 12 1.18
(1.05, 1.32)
1.18
(1.05, 1.33)
1.18
(1.00, 1.39)
Trimethoprim/
Sulfamethoxazole
   Sulfamethoxazole 800 Trimethoprim/
160 Sulfamethoxazole q12h, 7 days
400 q6h, 7 days 12 1.01
(0.95, 1.08)
1.05
(1.01, 1.09)
1.05
(0.97, 1.14)
Vardenafil 10 single dose 800 three times daily 18 See text below for discussion of interaction.
Zidovudine 200 three times daily, 7 days 1000 three times daily, 7 days 12 0.89
(0.73, 1.09)
1.17
(1.07, 1.29)
1.51
(0.71, 3.20)
n=4
Zidovudine/
Lamivudine
   Zidovudine 200/150 three times daily, 7 days 800 three times daily, 7 days 6, 7 1.23
(0.74, 2.03)
1.39
(1.02, 1.89)
1.08
(0.77, 1.50)
n=5, 5
Zidovudine/
Lamivudine
   Lamivudine 200/150 three times daily, 7 days 800 three times daily, 7 days 6, 7 0.73
(0.52, 1.02)
0.91
(0.66, 1.26)
0.88
(0.59, 1.33)


Table name:
Table 25: Clinically Important Drug Interactions with ABILIFY:
Concomitant Drug Name or Drug Class Clinical Rationale Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) The concomitant use of ABILIFY with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of ABILIFY alone [see CLINICAL PHARMACOLOGY (12.3)]. With concomitant use of ABILIFY with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the ABILIFY dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin) The concomitant use of ABILIFY and carbamazepine decreased the exposure of aripiprazole compared to the use of ABILIFY alone [see CLINICAL PHARMACOLOGY (12.3)]. With concomitant use of ABILIFY with a strong CYP3A4 inducer, consider increasing the ABILIFY dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Antihypertensive Drugs Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.7)].
Benzodiazepines (e.g., lorazepam) The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.7)] Monitor sedation and blood pressure. Adjust dose accordingly.


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function.
Drugs that may alter T4 and T3 serum transport - but FT4 concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin/Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens/Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non-Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4 . Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ³ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias
and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123 I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 3 Includes clinically significant drug interactions with buprenorphine and naloxone sublingual tablets
Benzodiazepines
Clinical Impact: There have been a number of reports regarding coma and death associated with the misuse and abuse of the combination of buprenorphine and benzodiazepines. In many, but not all of these cases, buprenorphine was misused by self-injection of crushed buprenorphine tablets. Preclinical studies have shown that the combination of benzodiazepines and buprenorphine altered the usual ceiling effect on buprenorphine-induced respiratory depression, making the respiratory effects of buprenorphine appear similar to those of full opioid agonists.
Intervention: Closely monitor patients with concurrent use of Buprenorphine and Naloxone Sublingual Tablets and benzodiazepines. Warn patients that it is extremely dangerous to self-administer benzodiazepines while taking Buprenorphine and Naloxone Sublingual Tablets, and warn patients to use benzodiazepines concurrently with Buprenorphine and Naloxone Sublingual Tablets only as directed by their healthcare provider.
Non-Benzodiazepine Central Nervous System (CNS) Depressants
Clinical Impact: Due to additive pharmacologic effects, the concomitant use of non-benzodiazepine CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.2, 5.3)].
Examples: Alcohol, non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and other opioids.
Inhibitors of CYP3A4
Clinical Impact: The concomitant use of buprenorphine and CYP3A4 inhibitors can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of Buprenorphine and Naloxone Sublingual Tablets is achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the buprenorphine plasma concentration will decrease [see Clinical Pharmacology (12.3)], potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to buprenorphine.
Intervention: If concomitant use is necessary, consider dosage reduction of Buprenorphine and Naloxone Sublingual Tablets until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the Buprenorphine and Naloxone Sublingual Tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)
CYP3A4 Inducers
Clinical Impact: The concomitant use of buprenorphine and CYP3A4 inducers can decrease the plasma concentration of buprenorphine [see Clinical Pharmacology (12.3)], potentially resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the buprenorphine plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both therapeutic effects and adverse reactions and may cause serious respiratory depression.
Intervention: If concomitant use is necessary, consider increasing the Buprenorphine and Naloxone Sublingual Tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider Buprenorphine and Naloxone Sublingual Tablets dosage reduction and monitor for signs of respiratory depression.
Examples: Rifampin, carbamazepine, phenytoin
Antiretrovirals: Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Clinical Impact: Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are metabolized principally by CYP3A4. Efavirenz, nevirapine, and etravirine are known CYP3A inducers, whereas delaviridine is a CYP3A inhibitor. Significant pharmacokinetic interactions between NNRTIs (e.g., efavirenz and delavirdine) and buprenorphine have been shown in clinical studies, but these pharmacokinetic interactions did not result in any significant pharmacodynamic effects.
Intervention: Patients who are on chronic Buprenorphine and Naloxone Sublingual Tablets treatment should have their dose monitored if NNRTIs are added to their treatment regimen.
Examples: efavirenz, nevirapine, etravirine, delavirdine
Antiretrovirals: Protease inhibitors (PIs)
Clinical Impact: Studies have shown some antiretroviral protease inhibitors (PIs) with CYP3A4 inhibitory activity (nelfinavir, lopinavir/ritonavir, ritonavir) have little effect on buprenorphine pharmacokinetic and no significant pharmacodynamic effects. Other PIs with CYP3A4 inhibitory activity (atazanavir and atazanavir/ritonavir) resulted in elevated levels of buprenorphine and norbuprenorphine, and patients in one study reported increased sedation. Symptoms of opioid excess have been found in post-marketing reports of patients receiving buprenorphine and atazanavir with and without ritonavir concomitantly.
Intervention: Monitor patients taking Buprenorphine and Naloxone Sublingual Tablets and atazanavir with and without ritonavir, and reduce dose of Buprenorphine and Naloxone Sublingual Tablets if warranted.
Examples: atazanavir, ritonavir
Antiretrovirals: Nucleoside reverse transcriptase inhibitors (NRTIs)
Clinical Impact: Nucleoside reverse transcriptase inhibitors (NRTIs) do not appear to induce or inhibit the P450 enzyme pathway, thus no interactions with buprenorphine are expected.
Intervention: None
Serotonergic Drugs
Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Buprenorphine and Naloxone Sublingual Tablets if serotonin syndrome is suspected.
Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma).
Intervention: The use of Buprenorphine and Naloxone Sublingual Tablets is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples: phenelzine, tranylcypromine, linezolid
Muscle Relaxants
Clinical Impact: Buprenorphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention: Monitor patients receiving muscle relaxants and Buprenorphine and Naloxone Sublingual Tablets for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Buprenorphine and Naloxone Sublingual Tablets and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact: The concomitant use of anticholinergic drugs may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when Buprenorphine and Naloxone Sublingual Tablets are used concomitantly with anticholinergic drugs.


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
 Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration  Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
 Drugs that may alter T 4 and T 3 metabolism
 Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
NA = Not available/reported
Digoxin concentrations increased greater than 50%
   Digoxin Serum   
Concentration Increase
   Digoxin AUC Increase Recommendations
Amiodarone 70% NA Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring.
Captopril 58% 39%
Clarithromycin NA 70%
Dronedarone NA 150%
Gentamicin 129-212% NA
Erythromycin 100% NA
Itraconazole 80% NA
Lapatinib NA 180%
Nitrendipine 57% 15%
Propafenone NA 60-270%
Quinidine 100% NA
Ranolazine 50% NA
Ritonavir NA 86%
Telaprevir 50% 85%
Tetracycline 100% NA
Verapamil 50-75% NA
Digoxin concentrations increased less than 50%
Atorvastatin 22% 15% Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring.
Carvedilol 16% 14%
Conivaptan 33% 43%
Diltiazem 20% NA
Indomethacin 40% NA
Nefazodone 27% 15%
Nifedipine 45% NA
Propantheline 24% 24%
Quinine NA 33%
Rabeprazole 29% 19%
Saquinavir 27% 49%
Spironolactone      25% NA
Telmisartan 20-49% NA
Ticagrelor 31% 28%
Tolvaptan 30% 20%
Trimethoprim 22-28% NA
Digoxin concentrations increased, but magnitude is unclear
Alprazolam, azithromycin, cyclosporine, diclofenac, diphenoxylate, epoprostenol, esomeprazole, ibuprofen, ketoconazole, lansoprazole, metformin, omeprazole Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin concentrations decreased
Acarbose, activated charcoal, albuterol, antacids, certain cancer chemotherapy or radiation therapy, cholestyramine, colestipol, extenatide, kaolin-pectin, meals high in bran, metoclopramide, miglitol, neomycin, penicillamine, phenytoin, rifampin, St. John’s Wort, sucralfate and sulfasalazine Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20-40% as necessary.


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Interacting Agents 
Prescribing Recommendations 
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, 
posaconazole, voriconazole, erythromycin, clarithromycin, 
telithromycin, HIV protease inhibitors, boceprevir, telaprevir, 
nefazodone, cobicistatcontaining products), gemfibrozil, 
cyclosporine, danazol 
 Contraindicated with simvastatin 
Verapamil, diltiazem, dronedarone
Do not exceed 10 mg simvastatin daily 
Amiodarone, amlodipine, ranolazine
Do not exceed 20 mg simvastatin daily 
Lomitapide
For patients with HoFH, do not exceed 
20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice 
Avoid grapefruit juice  


Table name:
Table 7: Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology (12.3)]
Drug/Drug Class
(Mechanism of Interaction by the Drug)
Voriconazole Plasma Exposure
(Cmax and AUCτ after
200 mg q12h)
Recommendations for Voriconazole Dosage Adjustment/Comments
RifampinResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg q12h voriconazole to healthy subjects and Rifabutin
(CYP450 Induction)
Significantly Reduced Contraindicated
Efavirenz (400 mg q24h)Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects
(CYP450 Induction)
Significantly Reduced Contraindicated
Efavirenz (300 mg q24h)
(CYP450 Induction)
Slight Decrease in AUC τ When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h) (CYP450 Induction) Significantly Reduced Contraindicated
Low-dose Ritonavir (100 mg q12h) (CYP450 Induction) Reduced Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Carbamazepine
(CYP450 Induction)
Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction Contraindicated
Long Acting Barbiturates
(CYP450 Induction)
Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction Contraindicated
Phenytoin
(CYP450 Induction)
Significantly Reduced Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg)
St. John's Wort
(CYP450 inducer; P-gp inducer)
Significantly Reduced Contraindicated
Oral Contraceptives
containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)
Increased Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole (CYP2C9, CYP2C19 and CYP3A4 Inhibition) Significantly Increased Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole.
Other HIV Protease Inhibitors
(CYP3A4 Inhibition)
In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir
     
In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors
(CYP3A4 Inhibition or CYP450 Induction)
In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to voriconazole
     
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs
(Decreased Plasma Exposure)
Careful assessment of voriconazole effectiveness


Table name:
Drugs That Interfere with Hemostasis
Clinical Impact: Indomethacin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of indomethacin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of indomethacin with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ see Warnings and Precautions ( 5.11 )].
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ see Warnings and Precautions ( 5.2 ) ].
Intervention: Concomitant use of indomethacin capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions ( 5.11 )].Indomethacin is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: During concomitant use of indomethacin capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.During concomitant use of indomethacin capsules and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ see Warnings and Precautions ( 5.6 )].When these drugs are administered concomitantly, patients should be adequately hydrated.  Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.It has been reported that the addition of triamterene to a maintenance schedule of Indomethacin resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin and triamterene should not be administered together.Both indomethacin and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently [ see Warnings and Precautions ( 5.6 )].  
Intervention: Indomethacin and triamterene should not be administered together. During concomitant use of indomethacin capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects. Be aware that indomethacin and potassium-sparing diuretics may both be associated with increased serum potassium levels. [ see Warnings and Precautions ( 5.6 )].  
Digoxin  
Clinical Impact: The concomitant use of indomethacin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.  
Intervention: During concomitant use of indomethacin capsules and digoxin, monitor serum digoxin levels.  
Lithium  
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.  
Intervention: During concomitant use of indomethacin capsules and lithium, monitor patients for signs of lithium toxicity.  
Methotrexate  
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).  
Intervention: During concomitant use of indomethacin capsules and methotrexate, monitor patients for methotrexate toxicity.  
Cyclosporine  
Clinical Impact: Concomitant use of indomethacin capsules and cyclosporine may increase cyclosporine's nephrotoxicity.  
Intervention: During concomitant use of indomethacin capsules and cyclosporine, monitor patients for signs of worsening renal function.  
NSAIDs and Salicylates  
Clinical Impact: Concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ see Warnings and Precautions ( 5.2 )]. Combined use with diflunisal may be particularly hazardous because diflunisal causes significantly higher plasma levels of indomethacin [see Clinical Pharmacology ( 12.3 )].In some patients, combined use of indomethacin and diflunisal has been associated with fatal gastrointestinal hemorrhage.  
Intervention: The concomitant use of indomethacin with other NSAIDs or salicylates, especially diflunisal, is not recommended.  
Pemetrexed  
Clinical Impact: Concomitant use of indomethacin capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).  
Intervention: During concomitant use of indomethacin capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.  
Probenecid  
Clinical Impact: When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased.  
Intervention: During the concomitant use of indomethacin and probenecid, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect.  When increases in the dose of indomethacin are made, they should be made carefully and in small increments.  


Table name:
Effects on steady-state fexofenadine pharmacokinetics after 7 days of co-administration with fexofenadine hydrochloride 120 mg every 12 hours in healthy adult subjects (n=24)
Concomitant Drug CmaxSS
(Peak plasma concentration)
AUCss(0–12h)
(Extent of systemic exposure)
Erythromycin
(500 mg every 8 hrs)
+82% +109%
  
Ketoconazole
(400 mg once daily)
+135% +164%


Table name:
Inhibitors of CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6
Clinical Impact: Methadone undergoes hepatic N-demethylation by several cytochrome P450 (CYP) isoforms, including CYP3A4, CYP2B6, CYP2C19, CYP2C9, and CYP2D6. The concomitant use of methadone hydrochloride tablets and CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitors can increase the plasma concentration of methadone, resulting in increased or prolonged opioid effects, and may result in a fatal overdose, particularly when an inhibitor is added after a stable dose of methadone hydrochloride tablets is achieved. These effects may be more pronounced with concomitant use of drugs that inhibit more than one of the CYP enzymes listed above. After stopping a CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitor, as the effects of the inhibitor decline, the methadone plasma concentration can decrease [see Clinical Pharmacology (12.3) ], resulting in decreased opioid efficacy or withdrawal symptoms in patients physically dependent on methadone.
Intervention: If concomitant use is necessary, consider dosage reduction of methadone hydrochloride tablets until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitor is discontinued, follow patients for signs of opioid withdrawal and consider increasing the methadone hydrochloride tablets dosage until stable drug effects are achieved.
Examples Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir), fluconazole, fluvoxamine, Some selective serotonin reuptake inhibitors (SSRIs) (e.g., sertraline, fluvoxamine)
Inducers of CYP3A4, CYP2B6, CYP2C19, or CYP2C9
Clinical Impact: The concomitant use of methadone hydrochloride tablets and CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers can decrease the plasma concentration of methadone [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of withdrawal symptomsin patients physically dependent on methadone. These effects could be more pronouncedwith concomitant use of drugs that can induce multiple CYP enzymes.After stopping a CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducer, as the effects ofthe inducer decline, the methadone plasma concentration can increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects andadverse reactions, and may cause serious respiratory depression, sedation, or death.
Intervention: If concomitant use is necessary, consider increasing the methadone hydrochloride tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducer is discontinued, consider methadone hydrochloride tablets dosage reduction and monitor for signs of respiratory depression and sedation.
Examples: Rifampin, carbamazepine, phenytoin, St. John’s Wort, Phenobarbital
Benzodiazepines and other Central Nervous System (CNS) Depressants
Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death.
Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.6) ].
Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Potentially Arrhythmogenic Agents
Clinical Impact: Pharmacodynamic interactions may occur with concomitant use of methadone and potentially arrhythmogenic agents or drugs capable of inducing electrolyte disturbances (hypomagnesemia, hypokalemia).
Intervention: Monitor patients closely for cardiac conduction changes.
Examples: Drugs known to have potential to prolong QT interval: Class I and III antiarrhythmics, some neuroleptics and tricyclic antidepressants, and calcium channel blockers. Drugs capable of inducing electrolyte disturbances: Diuretics, laxatives, and, in rare cases, mineralocortocoid hormones.
Serotonergic Drugs
Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Warnings and Precautions (5.8) ].
Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue methadone hydrochloride tablets if serotonin syndrome is suspected.
Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome [see Warnings and Precautions (5.8)] or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)].
Intervention: The use of methadone hydrochloride tablets is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact: May reduce the analgesic effect of methadone hydrochloride tablets and/or precipitate withdrawal symptoms.
Intervention: Avoid concomitant use.
Examples: butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact: Methadone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of methadone hydrochloride tablets and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when Methadone hydrochloride tablets are used concomitantly with anticholinergic drugs.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Inhibitors of CYP3A4
Clinical Impact: The concomitant use of OTFC and CYP3A4 inhibitors can increase the plasma concentration of fentanyl, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of OTFC is achieved [se e Warnings and Precautions ( 5.3 )]. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the fentanyl plasma concentration will decrease [ see Clinical Pharmacology ( 12.3 )], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to fentanyl.
Intervention: If concomitant use is necessary, consider dosage reduction of OTFC until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the OTFC dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir), grapefruit juice.
CYP3A4 Inducers
Clinical Impact: The concomitant use of OTFC and CYP3A4 inducers can decrease the plasma concentration of fentanyl [ see Clinical Pharmacology ( 12.3 )], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to fentanyl [ see Warnings and Precautions ( 5.3 )]. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the fentanyl plasma concentration will increase [ see Clinical Pharmacology ( 12.3 )], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.
Intervention: If concomitant use is necessary, consider increasing the OTFC dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider OTFC dosage reduction and monitor for signs of respiratory depression.
Examples: Rifampin, carbamazepine, phenytoin
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death.
Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions ( 5.4 )].
Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Warnings and Precautions ( 5.10 )].
Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue OTFC if serotonin syndrome is suspected.
Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome [se e Warnings and Precautions ( 5.10 )] or opioid toxicity (e.g., respiratory depression, coma) [ see Warnings and Precautions ( 5.1 )].
Intervention: The use of OTFC is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples: Phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact: May reduce the analgesic effect of OTFC and/or precipitate withdrawal symptoms.
Intervention: Avoid concomitant use.
Examples: Butorphanol, nalbuphine, pentazocine, buprenorphrine
Muscle Relaxants
Clinical Impact: Fentanyl may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of OTFC and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when OTFC is used concomitantly with anticholinergic drugs.


Table name:
a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
b = Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated.

AED Co-administered
AED Concentration
Topiramate Concentration
Phenytoin
NC or 25% increasea
48% decrease
Carbamazepine (CBZ)
NC
40% decrease
CBZ epoxideb
NC
NE
Valproic acid
11% decrease
14% decrease
Phenobarbital
NC
NE
Primidone
NC
NE
Lamotrigine
NC at TPM doses up to 400 mg/day
13% decrease


Table name:
AED  Co - administered
AED  Concentration
Topiramate  Concentration
Phenytoin
NCor25%increase a
48%decrease
Carbamazepine(CBZ)
NC
40%decrease
CBZepoxide b
NC 
            NE
Valproic acid
11%decrease
14%decrease
Phenobarbital
NC
            NE
Primidone
NC
           NE
Lamotrigine
NCatTPM dosesupto400  mg/day 
         13%decrease


Table name:
Drug Interactions Associated with Increased Risk of  Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice Avoid grapefruit juice


Table name:
Table 7. Effect of Voriconazole on Pharmacokinetics of Other Drugs [see Clinical Pharmacology (12.3)]
Drug/Drug Class (Mechanism of Interaction by Voriconazole) Drug Plasma Exposure (Cmax and AUC τ) Recommendations for Drug Dosage Adjustment/Comments
SirolimusResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects (CYP3A4 Inhibition) Significantly Increased Contraindicated
Rifabutin (CYP3A4 Inhibition) Significantly Increased Contraindicated
Efavirenz (400 mg q24h)Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects (CYP3A4 Inhibition)
 
Efavirenz (300 mg q24h)
(CYP3A4 Inhibition)
Significantly Increased
 
Slight Increase in AUCτ
Contraindicated
 
When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High dose Ritonavir (400 mg q12h)(CYP3A4 Inhibition) No Significant Effect of Voriconazole on Ritonavir Cmax or AUCτ Contraindicated because of significant reduction of voriconazole Cmax and AUCτ
Low dose Ritonavir (100 mg q12h) Slight Decrease in Ritonavir Cmax and AUCτ Coadministration of voriconazole and low dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole Cmax and AUCτ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Contraindicated because of potential for QT prolongation and rare occurrence of Torsades de pointes
Ergot Alkaloids (CYP450 Inhibition) Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Contraindicated
Cyclosporine (CYP3A4 Inhibition) AUCτ Significantly Increased; No Significant Effect on Cmax When initiating therapy with voriconazole in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When voriconazole is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
MethadoneResults based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for 4 days voriconazole to subjects receiving a methadone maintenance dose (30 mg to 100 mg q24h) (CYP3A4 Inhibition) Increased Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed.
Fentanyl (CYP3A4 Inhibition) Increased Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7)].
Alfentanil (CYP3A4 Inhibition) Significantly Increased Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with voriconazole. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [see Drug Interactions (7)].
Oxycodone (CYP3A4 Inhibition) Significantly Increased Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7)].
NSAIDsNon-Steroidal Anti-Inflammatory Drug including, ibuprofen and diclofenac (CYP2C9 Inhibition) Increased Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed [see Drug Interactions (7)].
Tacrolimus (CYP3A4 Inhibition) Significantly Increased When initiating therapy with voriconazole in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazole is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin (CYP2C9 Inhibition) Significantly Increased Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition) Increased Monitoring for adverse events related to oral contraceptives is recommended during coadministration.
Warfarin (CYP2C9 Inhibition) Prothrombin Time Significantly Increased Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed.
Omeprazole (CYP2C19/3A4 Inhibition) Significantly Increased When initiating therapy with voriconazole in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors (CYP3A4 Inhibition) In Vivo Studies Showed No Significant Effects on Indinavir Exposure No dosage adjustment for indinavir when coadministered with voriconazole
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors (CYP3A4 Inhibition) A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to NNRTI
Benzodiazepines (CYP3A4 Inhibition) In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.
HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition) In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition) In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition) Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed.
Everolimus
(CYP3A4 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Concomitant administration of voriconazole and everolimus is not recommended.


Table name:
Drugs That Interfere with Hemostasis
Clinical Impact: • Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of naproxen or naproxen sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: Concomitant use of naproxen or naproxen sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen or naproxen sodium is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE-inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: • During concomitant use of naproxen or naproxen sodium and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of naproxen or naproxen sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen or naproxen sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact: The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of naproxen or naproxen sodium and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen or naproxen sodium and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of naproxen or naproxen sodium and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of naproxen or naproxen sodium and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of naproxen or naproxen sodium and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of naproxen or naproxen sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of naproxen or naproxen sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact: Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention: Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen or naproxen sodium is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed release tablets are not recommended.
Cholestyramine
Clinical Impact: Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention: Concomitant administration of cholestyramine with naproxen or naproxen sodium is not recommended.
Probenecid
Clinical Impact: Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention: Patients simultaneously receiving naproxen or naproxen sodium and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact: Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention: Patients simultaneously receiving naproxen or naproxen sodium and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.


Table name:
Interacting Drug Interaction
Theophylline Serious and fatal reactions. Avoid concomitant use. Monitor serum level. (5.9, 7)
Warfarin Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding. (7)
Antidiabetic agents Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose. (7)
Phenytoin Monitor phenytoin level (7)
Methotrexate Monitor for methotrexate toxicity (7)
Cyclosporine May increase serum creatinine. Monitor serum creatinine. (7)
Multivalent cation-containing products including antacids, metal cations or didanosine Decreased CIPRO absorption. Take 2 hours before or 6 hours after CIPRO (2.2, 7)


Table name:
Concomitant Drug Name or Drug Class
Clinical Rationale
Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) 
The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].
With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)
The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].
With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Antihypertensive Drugs
Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.
Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.8)]. 
Benzodiazepines (e.g., lorazepam)
The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.8)]
Monitor sedation and blood pressure. Adjust dose accordingly.


Table name:
Table 3Drugs that Can Increase the Risk of Bleeding
Drug  Class
Specific  Drugs
Anticoagulants 
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin 
Antiplatelet Agents 
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine 
Nonsteroidal Anti-Inflammatory Agents 
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac 
Serotonin Reuptake Inhibitors 
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone 


Table name:
Table 5: Drugs having clinically important interactions with amphetamines.
MAO Inhibitors (MAOI)
Clinical Impact MAOI antidepressants slow amphetamine metabolism, increasing amphetamines effect on the release of norepinephrine and other monoamines from adrenergic nerve endings causing headaches and other signs of hypertensive crisis. Toxic neurological effects and malignant hyperpyrexia can occur, sometimes with fatal results.
Intervention Do not administer ADZENYS XR-ODT during or within 14 days following the administration of MAOI [see Contraindications (4) ].
Examples selegiline, isocarboxazid, phenelzine, tranylcypromine
Serotonergic Drugs
Clinical Impact The concomitant use of ADZENYS XR-ODT and serotonergic drugs increases the risk of serotonin syndrome.
Intervention Initiate with lower doses and monitor patients for signs and symptoms of serotonin syndrome, particularly during ADZENYS XR-ODT initiation or dosage increase. If serotonin syndrome occurs, discontinue ADZENYS XR-ODT and the concomitant serotonergic drug(s) [see Warnings and Precautions (5.7)].
Examples selective serotonin reuptake inhibitors (SSRI), serotonin norepinephrine reuptake inhibitors (SNRI), triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John's Wort
Alkalinizing Agents
Clinical Impact Increase blood levels and potentiate the action of amphetamine.
Intervention Co-administration of ADZENYS XR-ODT and gastrointestinal alkalinizing agents should be avoided.
Examples Gastrointestinal alkalinizing agents (e.g., sodium bicarbonate).
Urinary alkalinizing agents (e.g., acetazolamide, some thiazides).
Acidifying Agents
Clinical Impact Lower blood levels and efficacy of amphetamines.
Intervention Increase dose based on clinical response.
Examples Gastrointestinal acidifying agents (e.g., guanethidine, reserpine, glutamic acid HCl, ascorbic acid).
Tricyclic Antidepressants
Clinical Impact May enhance the activity of tricyclic or sympathomimetic agents causing striking and sustained increases in the concentration of d-amphetamine in the brain; cardiovascular effects can be potentiated.
Intervention Monitor frequently and adjust or use alternative therapy based on clinical response.
Examples desipramine, protriptyline


Table name:
Drugs That May Potentiate Renal Dysfunction
  Antibiotics   Antineoplastics   Anti-Inflammatory Drugs   Gastrointestinal Agents
 ciprofloxacin  melphalan  azapropazon  cimetidine
 gentamicin    colchicine  ranitidine
 tobramycin   Antifungals  diclofenac  
 trimethoprim  amphotericin B  naproxen   Immunosuppressives
 with  ketoconazole  sulindac  tacrolimus
 sulfamethoxazole      
 vancomycin       Other Drugs
       fibric acid derivatives
       (e.g., bezafibrate,
       fenofibrate)                   
       methotrexate


Table name:
Table II. Clinically significant drug interactions with theophylline.Refer to PRECAUTIONS, Drug Interactions for further information regarding table.
 Drug  Type of Interaction  EffectAverage effect on steady-state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.
 Adenosine  Theophylline blocks adenosine receptors.  Higher doses of adenosine may be required to achieve desired effect.
 Alcohol  A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours.  30% increase
 Allopurinol  Decreases theophylline clearance at allopurinol doses ≥600 mg/day.  25% increase
 Aminoglutethimide  Increases theophylline clearance by induction of microsomal enzyme activity.  25% decrease
 Carbamazepine  Similar to aminoglutethimide.  30% decrease
 Cimetidine  Decreases theophylline clearance by inhibiting cytochrome P450 1A2.  70% increase
 Ciprofloxacin  Similar to cimetidine.  40% increase
 Clarithromycin  Similar to erythromycin.  25% increase
 Diazepam  Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors.  Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
 Disulfiram  Decreases theophylline clearance by inhibiting hydroxylation and demethylation.  50% increase
 Enoxacin  Similar to cimetidine.  300% increase
 Ephedrine  Synergistic CNS effects  Increased frequency of nausea, nervousness, and insomnia.
 Erythromycin  Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3.  35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
 Estrogen  Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown.  30% increase
 Flurazepam  Similar to diazepam.  Similar to diazepam.
 Fluvoxamine  Similar to cimetidine.  Similar to cimetidine.
 Halothane  Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines.  Increased risk of ventricular arrhythmias.
 Interferon, human recombinant alpha-A  Decreases theophylline clearance.  100% increase
 Isoproterenol (IV)  Increase theophylline clearance.  20% increase
 Ketamine  Pharmacologic  May lower theophylline seizure threshold.
 Lithium  Theophylline increases renal lithium clearance.  Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
 Lorazepam  Similar to diazepam.  Similar to diazepam.
 Methotrexate (MTX)  Decreases theophylline clearance.  20% increase after low dose MTX, higher dose MTX may have a greater effect.
 Mexiletine  Similar to disulfiram.  80% increase
 Midazolam  Similar to diazepam.  Similar to diazepam.
 Moricizine  Increases theophylline clearance.  25% decrease
 Pancuronium  Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition.  Larger dose of pancuronium may be required to achieve neuromuscular blockade.
 Pentoxifylline  Decreases theophylline clearance.  30% increase
 Phenobarbital (PB)  Similar to aminoglutethimide.  25% decrease after two weeks of concurrent PB.
 Phenytoin  Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption.  Serum theophylline and phenytoin concentrations decrease about 40%.
 Propafenone  Decreases theophylline clearance and pharmacologic interaction.  40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
 Propranolol  Similar to cimetidine and pharmacologic interaction.  100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
 Rifampin  Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity.  20 to 40% decrease
 Sulfinpyrazone  Increase theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline.  20% increase
 Tacrine  Similar to cimetidine, also increases renal clearance of theophylline.  90% increase
 Thiabendazole  Decreases theophylline clearance.  190% increase
 Ticlopidine  Decreases theophylline clearance.  60% increase
 Troleandomycin  Similar to erythromycin.  33 to 100% increase depending on troleandomycin dose.
 Verapamil  Similar to disulfiram.  20% increase


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.11, 7.3)


Table name:
Drug Description
Corticosteroids Decreases plasma salicylate level; Tapering doses of steroids may promote salicylism
Ammonium Sulfate Increases plasma salicylate level


Table name:
Table 4: Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table 5 for Magnitude of Interaction.
Drug Name Effect on Concentration of Nevirapine or Concomitant Drug Clinical Comment
HIV Antiviral Agents: Protease Inhibitors (PIs)
Atazanavir/RitonavirThe interaction between nevirapine and the drug was evaluated in a clinical study. All other drug interactions shown are predicted. ↓ Atazanavir ↑ Nevirapine Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures.
Fosamprenavir ↓ Amprenavir ↑ Nevirapine Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.  
Fosamprenavir/Ritonavir ↓ Amprenavir ↑ Nevirapine No dosing adjustments are required when nevirapine is co-administered with 700 mg/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied.
Indinavir ↓ Indinavir The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established.
Lopinavir/Ritonavir ↓ Lopinavir Dosing in adult patients: A dose adjustment of lopinavir/ritonavir to 500 mg/125 mg tablets twice daily or 533 mg/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.   Dosing in pediatric patients: Please refer to the Kaletra® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.
Nelfinavir ↓ Nelfinavir M8 Metabolite ↓ Nelfinavir Cmin The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established.
Saquinavir/Ritonavir The interaction between nevirapine and saquinavir/ritonavir has not been evaluated. The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz ↓ Efavirenz The appropriate doses of these combinations with respect to safety and efficacy have not been established.  
Delavirdine Etravirine Rilpivirine Plasma concentrations may be altered. Nevirapine should not be co-administered with another NNRTI as this combination has not been shown to be beneficial.
Hepatitis C Antiviral Agents
Boceprevir Plasma concentrations of boceprevir may be decreased due to induction of CYP3A4/5 by nevirapine. Nevirapine and boceprevir should not be co-administered because decreases in boceprevir plasma concentrations may result in a reduction in efficacy.
Telaprevir Plasma concentrations of telaprevir may be decreased due to induction of CYP3A4 by nevirapine and plasma concentrations of nevirapine may be increased due to inhibition of CYP3A4 by telaprevir. Nevirapine and telaprevir should not be co-administered because changes in plasma concentrations of nevirapine, telaprevir, or both may result in a reduction in telaprevir efficacy or an increase in nevirapine-associated adverse events.
Other Agents
Analgesics: Methadone ↓ Methadone Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Antiarrhythmics: Amiodarone, disopyramide, lidocaine Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Antibiotics: Clarithromycin ↓ Clarithromycin ↑ 14-OH clarithromycin Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.  
Rifabutin ↑ Rifabutin Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.  
Rifampin ↓ Nevirapine Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Anticonvulsants: Carbamazepine, clonazepam, ethosuximide Plasma concentrations of nevirapine and the anticonvulsant may be decreased. Use with caution and monitor virologic response and levels of anticonvulsants.
Antifungals: Fluconazole ↑ Nevirapine Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events.  
Ketoconazole ↓ Ketoconazole Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.  
Itraconazole ↓ Itraconazole Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug.
Antithrombotics: Warfarin Plasma concentrations may be increased. Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.
Calcium channel blockers: Diltiazem, nifedipine, verapamil Plasma concentrations may be decreased. Appropriate doses for these combinations have not been established.
Cancer chemotherapy: Cyclophosphamide Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Ergot alkaloids: Ergotamine Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Immunosuppressants: Cyclosporine, tacrolimus, sirolimus Plasma concentrations may be decreased. Appropriate doses for these combinations have not been established.
Motility agents: Cisapride Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Opiate agonists: Fentanyl Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Oral contraceptives: Ethinyl estradiol and Norethindrone ↓ Ethinyl estradiol ↓ Norethindrone Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended.


Table name:
Table 23: Clinically Important Drug Interactions with Aripiprazole:
Concomitant  Drug  Name  or  Drug  Class

Clinical  Rationale

Clinical  Recommendation

Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine)
The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [ see  CLINICAL  PHARMACOLOGY  ( 12 . 3 )].
With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [ see  DOSAGE  AND  ADMINISTRATION ( 2 . 7 )].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)
The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [ see  CLINICAL  PHARMACOLOGY  ( 12 . 3 )].
With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [ see  DOSAGE  AND  ADMINISTRATION ( 2 . 7 )].
Antihypertensive Drugs
Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.
Monitor blood pressure and adjust dose accordingly [ see  WARNINGS  AND  PRECAUTIONS  ( 5 . 7 )].
Benzodiazepines (e.g., lorazepam)
The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepamalone [ see  WARNINGS  AND  PRECAUTIONS  ( 5 . 7 )]
Monitor sedation and blood pressure. Adjust dose accordingly.



Table name: 250 mg (adults weighing at least 60 kg with creatinine clearance of at least 60 mL/min) 200 mg (adults weighing less than 60 kg with creatinine clearance of at least 60 mL/min)VIDEX and tenofovir disoproxil fumarate may be taken together in the fasted state. If tenofovir disoproxil fumarate is taken with food, VIDEX should be taken on an empty stomach (at least 30 minutes before food or 2 hours after food). Patients should be monitored for didanosine-associated toxicities and clinical response.
Table 8:      Established Drug Interactions with VIDEX
Drug Effect Clinical Comment
↑  Indicates increase.
↓  Indicates decrease.
a  The dosing recommendation for coadministration of VIDEX EC and tenofovir disoproxil fumarate with respect to meal consumption differs from that of VIDEX. See the complete prescribing information for VIDEX EC.
ciprofloxacin ↓ ciprofloxacin concentration Administer VIDEX at least 2 hours after or 6 hours before ciprofloxacin.
delavirdine ↓ delavirdine concentration Administer VIDEX 1 hour after delavirdine.
ganciclovir ↑ didanosine concentration If there is no suitable alternative to ganciclovir, then use in combination with VIDEX with caution. Monitor for didanosine-associated toxicity.
indinavir ↓ indinavir concentration Administer VIDEX 1 hour after indinavir.
methadone ↓ didanosine concentration Do not coadminister methadone with VIDEX pediatric powder due to significant decreases in didanosine concentrations. If coadministration of methadone and didanosine is necessary, the recommended formulation of didanosine is VIDEX EC. Patients should be closely monitored for adequate clinical response when VIDEX EC is coadministered with methadone, including monitoring for changes in HIV RNA viral load.
nelfinavir No interaction 1 hour after didanosine Administer nelfinavir 1 hour after VIDEX.
tenofovir disoproxil fumarate ↑ didanosine concentration A dose reduction of VIDEX to the following dosage once daily is recommended.a


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion–the reduction is not sustained; therefore, hypothyroidism does not occur
  Dopamine / Dopamine Agonists
Glucocorticoids
Octreotide
  Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
  Aminoglutethimide
Amiodarone
Iodide(including iodine-containing
  Radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
  Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients.  The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
  Amiodarone
Iodide(including iodine-containing   
  Radiographic contrast agents)
  Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma).  Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
  Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
  Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism.  Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents.  Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport  - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
  Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
  Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
  Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
  Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4, and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result  in hypothyroidism
  Carbamazepine
Hydantoins
Phenobarbital
Rifampin
  Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5’-deiodinase activity
  Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
  Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4  levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
  Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
  Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
  Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors
  (SSRIs; e.g., Sertraline)
  Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of  tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
  Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
  Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
  Cardiac Glycosides   Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
  Cytokines
- Interferon-α
- Interleukin-2
  Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
  Growth Hormones
- Somatrem
- Somatropin
  Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
  Ketamine   Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
  Methylxanthine Bronchodilators
- (e.g., Theophylline)
  Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
  Radiographic Agents   Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
  Sympathomimetics   Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
  Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
  These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.


Table name:
Table 6: Clinically Significant Drug Interactions with Paricalcitol
CYP3A Inhibitors
Clinical Impact Paricalcitol is partially metabolized by CYP3A. Hence, exposure of paricalcitol will increase upon co-administration with strong CYP3A inhibitors such as but not limited to: boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole.
Intervention Dose adjustment of paricalcitol capsules may be necessary. Monitor closely for iPTH and serum calcium concentrations, if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor.
Cholestyramine
Clinical Impact Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of paricalcitol.
Intervention Recommend to take paricalcitol capsules at least 1 hour before or 4 to 6 hours after taking cholestyramine (or at as great an interval as possible) to avoid impeding absorption of paricalcitol.
Mineral Oil
Clinical Impact Mineral oil or other substances that may affect absorption of fat may influence the absorption of paricalcitol.
Intervention Recommend to take paricalcitol capsules at least 1 hour before or 4 to 6 hours after taking mineral oil (or at as great an interval as possible) to avoid affecting absorption of paricalcitol.


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
↓ = Decreased (induces lamotrigine glucuronidation).
↑ = Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.     
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and
150 mcg levonorgestrel
↓ lamotrigine


↓ levonorgestrel
Decreased lamotrigine concentrations approximately 50%.

Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide ↓ lamotrigine



? carbamazepine epoxide
Addition of carbamazepine decreases lamotrigine concentration approximately 40%.

May increase carbamazepine epoxide levels.
Lopinavir/ritonavir ↓ lamotrigine Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir ↓ lamotrigine Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine


? valproate
Increased lamotrigine concentrations slightly more than 2-fold.

There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.


Table name:
Table 14: Clinically Important Drug Interactions: Effect of other Drugs on Guanfacine Extended-Release
 Concomitant Drug Name or
Drug Class
 Clinical Rationale and Magnitude of Drug Interaction  Clinical Recommendation
 Strong and moderate CYP3A4 inhibitors, e.g., ketoconazole, fluconazole  Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected
resulting in an increase in exposure
 Consider dose reduction [see Dosage and administration ( 2.7 )]
 Strong and moderate CYP3A4 inducers, e.g., rifampin, efavirenz  Guanfacine is primarily metabolized by CYP3A4 and its
plasma concentrations can be significantly affected resulting in a decrease in exposure
 Consider dose increase
[see Dosage and administration ( 2.7 )]


Table name:
AED Coadministered
AED Concentration
Topiramate 
Concentration

a= Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
b= Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated
Phenytoin NC or 25% increasea 48% decrease
Carbamazepine (CBZ) NC 40% decrease
CBZ epoxideb NC NE
Valproic acid 11% decrease 14% decrease
Phenobarbital NC  NE
Primidone NC NE
Lamotrigine NC at TPM doses up to 400 mg/day 13% decrease


Table name:
Drug Description
Corticosteroids Decreases plasma salicylate level; tapering doses of steroids may promote salicylism
Ammonium Sulfate Increases plasma salicylate level


Table name:
Interacting Agents Prescribing Recommendations 
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, gemfibrozil, cyclosporine,danazol Contraindicated with simvastatin 
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine  Do not exceed 20 mg simvastatin daily
Grapefruit juice Avoid grapefruit juice


Table name:
Table 4 Other Potentially Significant Drug Interactions
Concomitant Drug Class or Food Noted or anticipated Outcome Clinical Comment
HMG-Co A Reductase Inhibitors:
atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin
Pharmacokinetic and/or pharmacodynamic interaction: the addition of one drug to a stable long-term regimen of the other has resulted in myopathy and rhabdomyolysis (including a fatality) Weigh the potential benefits and risks and carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during initial therapy; monitoring CPK (creatine phosphokinase) will not necessarily prevent the occurrence of severe myopathy.
Other Lipid Lowering Drugs:
fibrates, gemfibrozil
Digitalis Glycosides:
digoxin
P-gp substrate; rhabdomyolysis has been reported


Table name:
Effects on Steady-State Fexofenadine Pharmacokinetics After 7 Days of Co-Administration with Fexofenadine Hydrochloride 120 mg Every 12 Hours (two times the recommended twice daily dose) in Healthy Volunteers (n=24)
Concomitant Drug Cmax SS
(Peak plasma concentration)
AUCSS(0–12h)
(Extent of systemic exposure)
Erythromycin
(500 mg every 8 hrs)
+82% +109%
Ketoconazole
(400 mg once daily)
+135% +164%


Table name:
TABLE 2. Mean (± S.D.) Pharmacokinetic Parameters for Estradiol, Estrone, and Equilin Following Coadministration of Conjugated Estrogens 0.625 mg and PROMETRIUM Capsules 200 mg for 12 Days to Postmenopausal Women
a Total estrogens is the sum of conjugated and unconjugated estrogen.
  Conjugated Estrogens Conjugated Estrogens plus PROMETRIUM Capsules
Drug Cmax
(ng/mL)
Tmax
(hr)
AUC(0-24h)
(ng × h/mL)
Cmax
(ng/mL)
Tmax
(hr)
AUC(0-24h)
(ng × h/mL)
Estradiol 0.037
± 0.048
12.7
± 9.1
0.676
± 0.737
0.030
± 0.032
17.32
± 1.21
0.561
± 0.572
Estrone
Total a
3.68
± 1.55
10.6
± 6.8
61.3
± 26.36
4.93
± 2.07
7.5
± 3.8
85.9
± 41.2
Equilin
Total a
2.27
± 0.95
6.0
± 4.0
28.8
± 13.0
3.22
± 1.13
5.3
± 2.6
38.1
± 20.2


Table name:
Table 5 Effects on steady-state fexofenadine pharmacokinetics after 7 days of co-administration with fexofenadine hydrochloride 120 mg every 12 hours in healthy adult subjects (n=24)
Concomitant Drug CmaxSS
(Peak plasma concentration)
AUCss(0-12h)
(Extent of systemic exposure)
Erythromycin
(500 mg every 8 hrs)
+82% +109%
Ketoconazole
(400 mg once daily)
+135% +164%


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including: antacids, sucralfate, multivitamins Decreased moxifloxacin absorption. Take moxifloxacin hydrochloride tablet at least 4 hours before or 8 hours after these products. (2.2, 7.1, 12.3)
Warfarin Anticoagulant effect enhanced. Monitor prothrombin time/INR, and bleeding. (6, 7.2, 12.3)
Class IA and Class III antiarrhythmics: Proarrhythmic effect may be enhanced. Avoid concomitant use. (5.6, 7.5)
Antidiabetic agents Carefully monitor blood glucose. (5.11, 7.3)


Table name:
Concomitant Drug Name Effect of Carbamazepine on Other Drugs Clinical Recommendation
Lithium May increase the risk of neurotoxic side effects Use with intensive monitoring
Isoniazid May increase isoniazid-induced hepatotoxicity
Diuretics (e.g., hydrochlorothiazide, furosemide) May lead to symptomatic hyponatremia
Hormonal contraceptives (e.g., oral and levonorgestrel subdermal implant contraceptives) May render the contraceptives less effective because the plasma concentrations of the hormones may be decreased; breakthrough bleeding and unintended pregnancies have been reported Consider alternative or back-up methods of contraception
Neuromuscular blocking agents (e.g., pancuronium, vecuronium, rocuronium, and cisatracurium) Resistance to the neuromuscular blocking action of the non-depolarizing neuromuscular blocking agents Closely monitor patients for more rapid recovery from neuromuscular blockade than expected; infusion rate may need to be higher
 Delavirdine or other non-nucleoside reverse transcriptase inhibitors (NNRTIs)  Decrease in delavirdine or NNRTI levels  Contraindicated with carbamazepine


Table name:
Table 6 Clinically Important Drug Interactions
Concomitant Drug Name or Drug Class Clinical Rationale Clinical Recommendation
Tricyclic antidepressants Increase blood pressure and may counteract clonidine’s hypotensive effects Monitor blood pressure and adjust as needed
Antihypertensive drugs Potentiate clonidine’s hypotensive effects Monitor blood pressure and adjust as needed
CNS depressants Potentiate sedating effects Avoid use
Drugs that affect sinus node function or AV node conduction (e.g., digitalis, calcium channel blockers, beta blockers) Potentiate bradycardia and risk of AV block Avoid use


Table name:
Table 3: Drug Interactions: Pharmacokinetic Parameters for Coadministered Drug in the Presence of Indinavir (See PRECAUTIONS, Table 9 for Recommended Alterations in Dose or Regimen)
Coadministered drug Dose of Coadministered drug (mg) Dose of CRIXIVAN (mg) n Ratio (with/without CRIXIVAN) of Coadministered Drug
Pharmacokinetic Parameters
(90% CI); No Effect = 1.00
Cmax AUC Cmin
All interaction studies conducted in healthy, HIV-negative adult subjects, unless otherwise indicated.
Clarithromycin 500 twice daily,
7 days
800 three times daily, 7 days 12 1.19
(1.02, 1.39)
1.47
(1.30, 1.65)
1.97
(1.58, 2.46)
n=11
Efavirenz 200 once daily,
14 days
800 three times daily, 14 days 20 No significant change No significant change --
Ethinyl Estradiol
(ORTHO-NOVUM 1/35)Registered trademark of Ortho Pharmaceutical Corporation.
35 mcg, 8 days 800 three times daily, 8 days 18 1.02
(0.96, 1.09)
1.22
(1.15, 1.30)
1.37
(1.24, 1.51)
Isoniazid 300 once daily in the morning,
8 days
800 three times daily, 8 days 11 1.34
(1.12, 1.60)
1.12
(1.03, 1.22)
1.00
(0.92, 1.08)
MethadoneStudy conducted in subjects on methadone maintenance. 20-60 once daily in the morning,
8 days
800 three times daily, 8 days 12 0.93
(0.84, 1.03)
0.96
(0.86, 1.06)
1.06
(0.94, 1.19)
Norethindrone
(ORTHO-NOVUM 1/35)
1 mcg, 8 days 800 three times daily, 8 days 18 1.05
(0.95, 1.16)
1.26
(1.20, 1.31)
1.44
(1.32, 1.57)
Rifabutin
150 mg once daily in the morning, 11 days + indinavir compared to 300 mg once daily in the morning, 11 days alone
150 once daily in the morning,
10 days

300 once daily in the morning,
10 days
800 three times daily, 10 days


800 three times daily, 10 days
14



10
1.29
(1.05, 1.59)


2.34
(1.64, 3.35)
1.54
(1.33, 1.79)


2.73
(1.99, 3.77)
1.99
(1.71, 2.31)
n=13

3.44
(2.65, 4.46)
n=9
Ritonavir 100 twice daily,
14 days
800 twice daily,
14 days
10, 4Parallel group design; n for coadministered drug + indinavir, n for coadministered drug alone. 1.61
(1.13, 2.29)
1.72
(1.20, 2.48)
1.62
(0.93, 2.85)
200 twice daily,
14 days
800 twice daily,
14 days
9, 5 1.19
(0.85, 1.66)
1.96
(1.39, 2.76)
4.71
(2.66, 8.33)
n=9, 4
Saquinavir
   Hard gel formulation 600 single dose 800 three times daily, 2 days 6 4.7
(2.7, 8.1)
6.0
(4.0, 9.1)
2.9
(1.7, 4.7)C6hr
   Soft gel formulation 800 single dose 800 three times daily, 2 days 6 6.5
(4.7, 9.1)
7.2
(4.3, 11.9)
5.5
(2.2, 14.1)
   Soft gel formulation 1200 single dose 800 three times daily, 2 days 6 4.0
(2.7, 5.9)
4.6
(3.2, 6.7)
5.5
(3.7, 8.3)
Sildenafil 25 single dose 800 three times daily 6 See text below for discussion of interaction.
StavudineStudy conducted in HIV-positive subjects. 40 twice daily,
7 days
800 three times daily, 7 days 13 0.86
(0.73, 1.03)
1.21
(1.09, 1.33)
Not Done
Theophylline 250 single dose (on Days 1 and 7) 800 three times daily, 6 days (Days 2 to 7) 12, 4 0.88
(0.76, 1.03)
1.14
(1.04, 1.24)
1.13
(0.86, 1.49)
n=7, 3
Trimethoprim/
Sulfamethoxazole
   Trimethoprim 800 Trimethoprim/
160 Sulfamethoxazole q12h, 7 days
400 q6h, 7 days 12 1.18
(1.05, 1.32)
1.18
(1.05, 1.33)
1.18
(1.00, 1.39)
Trimethoprim/
Sulfamethoxazole
   Sulfamethoxazole 800 Trimethoprim/
160 Sulfamethoxazole q12h, 7 days
400 q6h, 7 days 12 1.01
(0.95, 1.08)
1.05
(1.01, 1.09)
1.05
(0.97, 1.14)
Vardenafil 10 single dose 800 three times daily 18 See text below for discussion of interaction.
Zidovudine 200 three times daily, 7 days 1000 three times daily, 7 days 12 0.89
(0.73, 1.09)
1.17
(1.07, 1.29)
1.51
(0.71, 3.20)
n=4
Zidovudine/
Lamivudine
   Zidovudine 200/150 three times daily, 7 days 800 three times daily, 7 days 6, 7 1.23
(0.74, 2.03)
1.39
(1.02, 1.89)
1.08
(0.77, 1.50)
n=5, 5
Zidovudine/
Lamivudine
   Lamivudine 200/150 three times daily, 7 days 800 three times daily, 7 days 6, 7 0.73
(0.52, 1.02)
0.91
(0.66, 1.26)
0.88
(0.59, 1.33)


Table name:

a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
b = Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated
AED Co-administered 
AED Concentration
Topiramate Concentration
Phenytoin 
NC or 25% increasea
48% decrease
Carbamazepine (CBZ)
NC 
40% decrease
CBZ epoxideb
NC
NE
Valproic acid 
11% decrease
14% decrease
Phenobarbital
NC
NE
Primidone 
NC
NE
Lamotrigine 
NC at TPM doses up to 400 mg/day
13% decrease


Table name:
AED Co-administered AED Concentration Topiramate Concentration
Phenytoin
NC or 25% increasea 48% decrease
Carbamazepine (CBZ) NC
40% decrease
CBZ epoxideb NC
NE
Valproic acid
11% decrease 14% decrease
Phenobarbital NC NE
Primidone
NC NE
Lamotrigine
NC at TPM doses up to 400 mg/day 13% decrease


Table name:
Bleeding   times 
Clinical   Impact: 
 Naproxen may decrease platelet aggregation and prolong bleeding time. 
Intervention: 
This effect should be kept in mind when bleeding times are determined. 
Porter-Silber   test 
Clinical   Impact: 
The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di­-nitrobenzene used in this assay. 
Intervention: 
Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen  be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used. 
Urinary   assays of 5-hydroxy indoleacetic acid (5HIAA) 
Clinical   Impact: 
Naproxen  may interfere with some urinary assays of 5-hydroxy  indoleacetic acid (5HIAA). 
Intervention: 
This  effect should be  kept in mind when  urinary  5-hydroxy  indoleacetic acid is determined. 


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine Decreased lamotrigine levels approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? CBZ epoxide May increase CBZ epoxide levels
Phenobarbital/Primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT) ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine Increased lamotrigine concentrations slightly more than 2-fold.
? valproate Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
Bleeding times
Clinical Impact: Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention: This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact: The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention: Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact: Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention: This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.


Table name:
Interacting Agents Prescribing Recommendations
Strong CYP3A4 Inhibitors, (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol Contraindicated with ezetimibe and simvastatin tablets
Verapamil, diltiazem, dronedarone Do not exceed ezetimibe and simvastatin tablets, 10 mg/10 mg daily
Amiodarone, amlodipine, ranolazine Do not exceed ezetimibe and simvastatin tablets, 10 mg/20 mg daily
Lomitapide For patients with HoFH, do not exceed 10 mg/20 mg ezetimibe and simvastatin tablets1
Grapefruit juice Avoid grapefruit juice


Table name:
Table 4: Drugs Having Clinically Important Interactions with Amphetamines
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact Concomitant use of MAOIs and CNS stimulants can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure.
Intervention Do not administer ADDERALL XR concomitantly or within 14 days after discontinuing MAOI [see CONTRAINDICATIONS (4) and WARNINGS AND PRECAUTIONS (5.6)].
Examples selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue
Serotonergic Drugs
Clinical Impact The concomitant use of ADDERALL XR and serotonergic drugs increases the risk of serotonin syndrome.
Intervention Initiate with lower doses and monitor patients for signs and symptoms of serotonin syndrome, particularly during ADDERALL XR initiation or dosage increase. If serotonin syndrome occurs, discontinue ADDERALL XR and the concomitant serotonergic drug(s) [see WARNINGS AND PRECAUTIONS (5.6)].
Examples selective serotonin reuptake inhibitors (SSRI), serotonin norepinephrine reuptake inhibitors (SNRI), triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John's Wort
CYP2D6 Inhibitors
Clinical Impact The concomitant use of ADDERALL XR and CYP2D6 inhibitors may increase the exposure of ADDERALL XR compared to the use of the drug alone and increase the risk of serotonin syndrome.
Intervention Initiate with lower doses and monitor patients for signs and symptoms of serotonin syndrome particularly during ADDERALL XR initiation and after a dosage increase. If serotonin syndrome occurs, discontinue ADDERALL XR and the CYP2D6 inhibitor [see WARNINGS AND PRECAUTIONS (5.6) and OVERDOSAGE (10)].
Examples paroxetine and fluoxetine (also serotonergic drugs), quinidine, ritonavir
Alkalinizing Agents
Clinical Impact Increase blood levels and potentiate the action of amphetamine.
Intervention Co-administration of ADDERALL XR and gastrointestinal or urinary alkalinizing agents should be avoided.
Examples Gastrointestinal alkalinizing agents (e.g., sodium bicarbonate). Urinary alkalinizing agents (e.g. acetazolamide, some thiazides).
Acidifying Agents
Clinical Impact Lower blood levels and efficacy of amphetamines.
Intervention Increase dose based on clinical response.
Examples Gastrointestinal acidifying agents (e.g., guanethidine, reserpine, glutamic acid HCl, ascorbic acid).
Urinary acidifying agents (e.g., ammonium chloride, sodium acid phosphate, methenamine salts).
Tricyclic Antidepressants
Clinical Impact May enhance the activity of tricyclic or sympathomimetic agents causing striking and sustained increases in the concentration of d-amphetamine in the brain; cardiovascular effects can be potentiated.
Intervention Monitor frequently and adjust or use alternative therapy based on clinical response.
Examples desipramine, protriptyline
Proton Pump Inhibitors
Clinical Impact Time to maximum concentration (Tmax) of amphetamine is decreased compared to when administered alone.
Intervention Monitor patients for changes in clinical effect and adjust therapy based on clinical response.
Examples omeprazole


Table name:
Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
Interacting Agents Prescribing Recommendations 
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, gemfibrozil, cyclosporine,danazol Contraindicated with simvastatin 
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine  Do not exceed 20 mg simvastatin daily
Grapefruit juice Avoid grapefruit juice


Table name:
Table 5: Effect of Other Drugs on VYVANSE
Concomitant Drug Name or Drug Class Clinical Rationale Clinical Recommendation
Acidifying and Alkalinizing Agents Ascorbic acid and other agents that acidify urine increase urinary excretion and decrease the half-life of amphetamine. Sodium bicarbonate and other agents that alkalinize urine decrease urinary excretion and extend the half-life of amphetamine. Adjust the dose accordingly [see Dosage and Administration (2.6)]


Table name:
Table 2: Clinically Relevant Interactions Affecting Drugs Co-Administered with Rabeprazole Sodium Delayed-Release Tablets
Antiretrovirals
Clinical Impact: The effect of PPI on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir, and nelfinavir) when used concomitantly with rabeprazole may reduce antiviral effect and promote the development of drug resistance. Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with rabeprazole may increase toxicity. There are other antiretroviral drugs which do not result in clinically relevant interactions with rabeprazole.
Intervention: Rilpivirine-containing products: Concomitant use with rabeprazole sodium rabeprazole sodium delayed-release tablets is contraindicated [see Contraindications (4)]. See prescribing information. Atazanavir: See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with rabeprazole sodium delayed-release tablets. See prescribing information for nelfinavir. Saquinavir: See the prescribing information for saquinavir and monitor for potential saquinavir toxicities. Other antiretrovirals: See prescribing information.
Warfarin
Clinical Impact: Increased INR and prothrombin time in patients receiving PPIs, including rabeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death [see Warnings and Precautions (5.2)].
Intervention: Monitor INR and prothrombin time. Dose adjustment of warfarin may be needed to maintain target INR range. See prescribing information for warfarin.
Methotrexate
Clinical Impact: Concomitant use of rabeprazole with methotrexate (primarily at high dose) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of methotrexate with PPIs have been conducted [see Warnings and Precautions (5.9)].
Intervention: A temporary withdrawal of rabeprazole sodium delayed-release tablets may be considered in some patients receiving high dose methotrexate administration.
Digoxin
Clinical Impact: Potential for increased exposure of digoxin [see Clinical Pharmacology (12.3)].
Intervention: Monitor digoxin concentrations. Dose adjustment of digoxin may be needed to maintain therapeutic drug concentrations. See prescribing information for digoxin.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole, itraconazole)
Clinical Impact: Rabeprazole can reduce the absorption of drugs due to its effect on reducing intragastric acidity.
Intervention: Mycophenolate mofetil (MMF): Co-administration of PPIs in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving PPIs and MMF. Use rabeprazole sodium delayed-release tablets with caution in transplant patients receiving MMF. See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact: Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions.
Intervention: See Contraindications and Warnings and Precautions in prescribing information for clarithromycin. See Drug Interactions in prescribing information for amoxicillin.


Table name:
Table 5. Established and Other Potentially Significant Drug Interactions
↓ = Decreased (induces lamotrigine glucuronidation).
↑ = Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.


Concomitant  Drug
Effect  on  Concentration  of  Lamotrigine  or  Concomitant  Drug


Clinical  Comment
Estrogen-containing oral
contraceptive
preparations containing
30 mcg ethinylestradiol
and 150 mcg
levonorgestrel
↓ lamotrigine

↓ levonorgestrel

Decreased lamotrigine concentrations approximately 50%.
Decrease in levonorgestrel component by 19%.

Carbamazepine and
carbamazepine epoxide

↓ lamotrigine


? carbamazepine epoxide

Addition of carbamazepine decreases lamotrigine concentration approximately
40%.
May increase carbamazepine epoxide levels.
Lopinavir/ritonavir 
↓ lamotrigine 
Decreased lamotrigine concentration approximately 50%. 
Atazanavir/ritonavir 
↓ lamotrigine 
Decreased lamotrigine AUC approximately 32%. 
Phenobarbital/Primidone
↓ lamotrigine

Decreased lamotrigine concentration approximately 40%.
Phenytoin
↓ lamotrigine

Decreased lamotrigine concentration approximately 40%.
Rifampin
↓ lamotrigine

Decreased lamotrigine AUC approximately 40%.
Valproate
↑ lamotrigine

? valproate
Increased lamotrigine concentrations slightly more than 2-fold.
There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 45.1, 7.1, 7.2, 7.3, 12.3)
   Interacting Agents    Prescribing Recommendations
   Strong CYP3A4 inhibitors (e.g.,Itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol
   Contraindicated with simvastatin
   Verapamil, diltiazem, dronedarone
   Do not exceed 10 mg simvastatin daily
   Amiodarone, amlodipine, ranolazine
   Do not exceed 20 mg simvastatin daily
   Grapefruit juice
   Avoid grapefruit juice


Table name:
Table 3 Clinically Significant Drug Interactions with Meloxicam
Drugs that Interfere with Hemostasis
Clinical Impact:

Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:

Monitor patients with concomitant use of MOBIC with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ see Warnings and Precautions ( 5.11) ].
Aspirin
Clinical Impact:

Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ see Warnings and Precautions ( 5.2) ].
Intervention:

Concomitant use of MOBIC and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions ( 5.11) ].

MOBIC is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, or Beta-Blockers
Clinical Impact:

NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:

During concomitant use of MOBIC and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of MOBIC and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ see Warnings and Precautions ( 5.6) ]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:

Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam.
Intervention:

During concomitant use of MOBIC with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ see Warnings and Precautions ( 5.6) ].
Lithium
Clinical Impact:

NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [ see Clinical Pharmacology ( 12.3) ].
Intervention:

During concomitant use of MOBIC and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:

Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:

During concomitant use of MOBIC and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:

Concomitant use of MOBIC and cyclosporine may increase cyclosporine's nephrotoxicity.
Intervention:

During concomitant use of MOBIC and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:

Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ see Warnings and Precautions ( 5.2) ].
Intervention:

The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:

Concomitant use of MOBIC and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:

During concomitant use of MOBIC and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.

Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.

In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended.


Table name:
Table 3 Clinically Significant Drug Interactions with Meloxicam
Drugs that Interfere with Hemostasis
Clinical Impact:
Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:
Monitor patients with concomitant use of meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact:
Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].
Intervention:
Concomitant use of meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)].
 
Meloxicam is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, or Beta-Blockers
Clinical Impact:
NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:
During concomitant use of meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:
Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam.
Intervention:
During concomitant use of meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Lithium
Clinical Impact:
NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [see Clinical Pharmacology (12.3)].
Intervention:
During concomitant use of meloxicam and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:
Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:
During concomitant use of meloxicam and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:
Concomitant use of meloxicam and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:
During concomitant use of meloxicam and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:
Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention:
The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:
Concomitant use of meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:
During concomitant use of meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.
 
Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
 
In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended.


Table name:
Table II. Clinically significant drug interactions with theophylline*.
 Drug  Type of Interaction  Effect **
 Adenosine  Theophylline blocks adenosine receptors.  Higher doses of adenosine may be required to achieve desired effect.
 Alcohol  A single large dose of alcohol (3 ml/kg of whiskey) decreases theophylline clearance for up to 24 hours.  30% increase
 Allopurinol  Decreases theophylline clearance at allopurinol doses ≥600 mg/day.  25% increase
 Aminoglutethimide  Increases theophylline clearance by induction of microsomal enzyme activity.  25% decrease
 Carbamazepine  Similar to aminoglutethimide.  30% decrease
 Cimetidine  Decreases theophylline clearance by inhibiting cytochrome P450 1A2.  70% increase
 Ciprofloxacin  Similar to cimetidine.  40% increase
 Clarithromycin  Similar to erythromycin.  25% increase
 Diazepam  Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors.  Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
 Disulfiram  Decreases theophylline clearance by inhibiting hydroxylation and demethylation.  50% increase
 Enoxacin  Similar to cimetidine.  300% increase
 Ephedrine  Synergistic CNS effects.  Increased frequency of nausea, nervousness, and insomnia.
 Erythromycin  Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3.  35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
 Estrogen  Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown.  30% increase
 Flurazepam  Similar to diazepam.  Similar to diazepam.
 Fluvoxamine  Similar to cimetidine.  Similar to cimetidine.
 Halothane  Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines.  Increased risk of ventricular arrhythmias.
 Interferon, human recombinant alpha-A  Decreases theophylline clearance.  100% increase
 Isoproterenol (IV)  Increases theophylline clearance.  20% decrease
 Ketamine  Pharmacologic  May lower theophylline seizure threshold.
 Lithium  Theophylline increases renal lithium clearance.  Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
 Lorazepam  Similar to diazepam.  Similar to diazepam.
 Methotrexate (MTX)  Decreases theophylline clearance.  20% increase after low dose MTX, higher dose MTX may have a greater effect.
 Mexiletine  Similar to disulfiram.  80% increase
 Midazolam  Similar to diazepam.  Similar to diazepam.
 Moricizine  Increases theophylline clearance.  25% decrease
 Pancuronium  Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition.  Larger dose of pancuronium may be required to achieve neuromuscular blockade.
 Pentoxifylline  Decreases theophylline clearance.  30% increase
 Phenobarbital (PB)  Similar to aminoglutethimide.  25% decrease after two weeks of concurrent PB.
 Phenytoin  Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption.  Serum theophylline and phenytoin concentrations decrease about 40%.
 Propafenone  Decreases theophylline clearance and pharmacologic interaction.  40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
 Propranolol  Similar to cimetidine and pharmacologic interaction.  100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
 Rifampin  Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity.  20 to 40% decrease
 Sulfinpyrazone  Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline.  20% decrease
 Tacrine  Similar to cimetidine, also increases renal clearance of theophylline.  90% increase
 Thiabendazole  Decreases theophylline clearance.  190% increase
 Ticlopidine  Decreases theophylline clearance.  60% increase
 Troleandomycin  Similar to erythromycin.  33 to 100% increase depending on troleandomycin dose.
 Verapamil  Similar to disulfiram.  20% increase
 *Refer to PRECAUTIONS, Drug Interactions for further information regarding table. ** Average effect on steady state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.


Table name:
*For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Interacting  Agents  Prescribing  Recommendations 
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol  Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily 
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily 
Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin daily*
Grapefruit juice  Avoid grapefruit juice 


Table name:
Table 2:   Examples of CYP450 Interactions with Warfarin
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Figure 2: Effect of venlafaxine on the pharmacokinetics interacting drugs and their active metabolites.


Table name:
Summary of AED interactions with topiramate ( 7.1).
AED Co-administered AED Concentration Topiramate Concentration
Phenytoin NC or 25% increase a 48% decrease
Carbamazepine (CBZ) NC 40% decrease
CBZ epoxide b NC NE
Valproic acid 11% decrease 14% decrease
Phenobarbital NC NE
Primidone NC NE
Lamotrigine NC at TPM doses up to 400mg/day 13% decrease


Table name:
Table 5. Drugs That May Decrease Conversion of T4 to T3
Potential impact: Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased.
Drug or Drug Class Effect
Beta-adrenergic antagonists
(e.g., Propranolol > 160 mg/day)
In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change, TSH levels remain normal, and patients are clinically euthyroid. Actions of particular beta-adrenergic antagonists may be impaired when a hypothyroid patient is converted to the euthyroid state.
Glucocorticoids
(e.g., Dexamethasone > 4 mg/day)
Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (See above).
Other drugs:
Amiodarone
Amiodarone inhibits peripheral conversion of levothyroxine (T4) to triiodothyronine (T3) and may cause isolated biochemical changes (increase in serum free-T4, and decreased or normal free-T3) in clinically euthyroid patients.


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide

Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide






Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T and T levels and increase TSH, although all values remain within normal limits in most patients. 4 3
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate










Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
  Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration   Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen





Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid


Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)





Administration of these agents with levothyroxine results in an initial transient increase in FT . Continued administration results in a decrease in serum T and normal FT and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T and T to TBG and transthyretin. An initial increase in serum FT , is followed by return of FT to normal levels with sustained therapeutic serum salicylate concentrations, although total-T levels may decrease by as much as 30%. 4 4 4 4 3 4 4 4
  Drugs that may alter T 4 and T 3 metabolism
  Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin


Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. 4
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)




Administration of these enzyme inhibitors decrease the peripheral conversion of T to T , leading to decreased T levels. However, serum T levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T and T levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T concentrations by 30% with minimal change in serum T levels. However, long-term glucocorticoid therapy may result in slightly decreased T and T levels due to decreased TBG production (see above). 4 3 3 4 3 4 3 4 3 4
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives

Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)


Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin




Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2

Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin

Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of I, I, and Tc. 123 131 99m
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics









These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 2       Effects of Paroxetine on Other Drugs
Concomitant
Drug Name


Effect of Paroxetine on
Other Drugs
Clinical Recommendations
Thioridazine



Increased plasma concentrations of thioridazine

Potential QTc prolongation
Concomitant use of thioridazine and BRISDELLE is
contraindicated.
Pimozide



Increased plasma concentrations
of pimozide. Potential QTc
prolongation
Concomitant use of pimozide and BRISDELLE is
contraindicated.
Tamoxifen


Reduced plasma concentrations
of active tamoxifen metabolite
Consider avoiding concomitant use of tamoxifen
and BRISDELLE.

Tricyclic
Antidepressant
(TCA)
(e.g., Desipramine)

Increased plasma concentrations
and elimination half-life
Plasma TCA concentrations may need to be
monitored and the dose of TCA may need to be
reduced if a TCA is co-administered with
BRISDELLE. Monitor tolerability.
Risperidone



Increased plasma concentrations
of risperidone
A lower dosage of risperidone may be necessary
(see the Full Prescribing Information for
risperidone). Monitor tolerability.
Atomoxetine



Increased exposure of
atomoxetine
A lower dosage of atomoxetine may be necessary
(see Full Prescribing Information for atomoxetine).
Monitor tolerability.
Drugs Highly Bound
to Plasma Protein
(e.g., Warfarin)

Increased free plasma
concentrations
The dosage of warfarin may need to be reduced.
Monitor tolerability and the International
Normalized Ratio.
Digoxin


Decreased plasma concentrations
of digoxin
Dosage of digoxin may need to be increased.
Monitor digoxin concentrations and clinical effect.
Theophylline



Increased plasma concentrations
of theophylline
Dosage of theophylline may need to be decreased.
Monitor theophylline concentrations and
tolerability.


Table name:
Drug Description of Interaction
Tolbutamide; Sulfonylureas Hypoglycemia potentiated
Methotrexate Decrease tubular reabsorption; clinical toxicity from methotrexate can result
Oral Anticoagulants Increased bleeding


Table name:
AED Coadministered AED Concentration Topiramate Concentration
Phenytoin
NC or 25% increase Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
48% decrease


Carbamazepine (CBZ)
NC
40% decrease
CBZ epoxide Is not administered but is an active metabolite of carbamazepine.
NC
NE
Valproic acid
11% decrease
14% decrease
Phenobarbital
NC
NE
Primidone
NC
NE
Lamotrigine
NC at TPM doses up to 400 mg/day
13% decrease


Table name:
Interacting Drug
Interaction
Theophylline
Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin
Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents
Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin
Monitor phenytoin level (7)
Methotrexate
Monitor for methotrexate toxicity (7)
Cyclosporine
May increase serum creatinine. Monitor serum creatinine (7)
Multivalent cation-containing products including antacids, metal cations or didanosine
Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin (7)


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
 Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration  Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
 Drugs that may alter T 4 and T 3 metabolism
 Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Antibiotics Anticonvulsants Other Drugs/DietarySupplements
nafcillin carbamazepine bosentan  St. John’s Wort
rifampin oxcarbazepine octreotide
phenobarbital orlistat
phenytoin sulfinpyrazone
terbinafine
ticlopidine


Table name:
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)   Avoid atorvastatin  
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) Do not exceed 40 mg atorvastatin daily


Table name:
Interacting Agents Prescribing Recommendations 
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone Avoid simvastatin 
Gemfibrozil, cyclosporine,danazol  Do not exceed 10 mg simvastatindaily 
Amiodarone, verapamil Do not exceed 20 mg simvastatin daily 
Diltiazem Do not exceed 40 mg simvastatin daily
Grapefruit juice Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Table 3 Clinically Significant Drug Interactions with Meloxicam
Drugs  that  Interfere  with  Hemostasis
Clinical  Impact :
Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.
Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. 
Intervention :
Monitor patients with concomitant use of meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ see  WARNINGS  AND  PRECAUTIONS  ( 5 . 11 )].
Aspirin
Clinical  Impact :
Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ see  WARNINGS  AND  PRECAUTIONS  ( 5 . 2 )].
Intervention :
Concomitant use of meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see  WARNINGS  AND  PRECAUTIONS  ( 5 . 11 )]. 

Meloxicam is not a substitute for low dose aspirin for cardiovascular protection.
ACE  Inhibitors Angiotensin  Receptor  Blockers or  Beta - Blockers
Clinical  Impact :
NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).
In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention :
During concomitant use of meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.
During concomitant use of meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ see  WARNINGS  AND  PRECAUTIONS  ( 5 . 6 )]. 
When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical  Impact :
Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam.
Intervention :
During concomitant use of meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ see  WARNINGS  AND  PRECAUTIONS  ( 5 . 6 )].
Lithium
Clinical  Impact :
NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [ see  CLINICAL  PHARMACOLOGY  ( 12 . 3 )].
Intervention :
During concomitant use of meloxicam and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical  Impact :
Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention :
During concomitant use of meloxicam and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical  Impact :
Concomitant use of meloxicam and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention :
During concomitant use of meloxicam and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs  and  Salicylates
Clinical  Impact :
Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ see  WARNINGS  AND  PRECAUTIONS  ( 5 . 2 )].
Intervention :
The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical  Impact :
Concomitant use of meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention :
During concomitant use of meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.
Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended.


Table name:
Table 8: Clinically Significant Drug Interactions with LANTUS
Drugs That May Increase the Risk of Hypoglycemia
Drugs: Antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, propoxyphene, salicylates, somatostatin analogs (e.g., octreotide), and sulfonamide antibiotics.
Intervention: Dose reductions and increased frequency of glucose monitoring may be required when LANTUS is co-administered with these drugs.
Drugs That May Decrease the Blood Glucose Lowering Effect of LANTUS
Drugs: Atypical antipsychotics (e.g., olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones
Intervention: Dose increases and increased frequency of glucose monitoring may be required when LANTUS is co-administered with these drugs.
Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of LANTUS
Drugs: Alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia.
Intervention: Dose adjustment and increased frequency of glucose monitoring may be required when LANTUS is co-administered with these drugs.
Drugs That May Blunt Signs and Symptoms of Hypoglycemia
Drugs: beta-blockers, clonidine, guanethidine, and reserpine
Intervention: Increased frequency of glucose monitoring may be required when LANTUS is co-administered with these drugs.


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
AED  Co - administered
AED  Concentration
Topiramate  Concentration
Phenytoin
NCor25%increase a
48%decrease
Carbamazepine(CBZ)
NC
40%decrease
CBZepoxide b
NC 
            NE
Valproic acid
11%decrease
14%decrease
Phenobarbital
NC
            NE
Primidone
NC
           NE
Lamotrigine
NCatTPM dosesupto400  mg/day 
         13%decrease


Table name:
Table 6 Clinically Important Drug Interactions
Concomitant Drug Name or Drug Class Clinical Rationale Clinical Recommendation
Tricyclic antidepressants Increase blood pressure and may counteract clonidine’s hypotensive effects Monitor blood pressure and adjust as needed
Antihypertensive drugs Potentiate clonidine’s hypotensive effects Monitor blood pressure and adjust as needed
CNS depressants Potentiate sedating effects Avoid use
Drugs that affect sinus node function or AV node conduction (e.g., digitalis, calcium channel blockers, beta blockers) Potentiate bradycardia and risk of AV block Avoid use


Table name:
Table 2. Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T4 and T3 serum transport - but FT4 concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors
(SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 5. Sevelamer Drug Interactions
Oral drugs for which sevelamer did not alter the pharmacokinetics when administered concomitantly
Digoxin
Enalapril
Iron
Metoprolol
Warfarin
Oral drugs that have demonstrated interaction with sevelamer and are to be dosed separately from sevelamer carbonate
 
Ciprofloxacin
Mycophenolate mofetil
Dosing Recommendations
Take at least 2 hours before or 6 hours after sevelamer
Take at least 2 hours before sevelamer


Table name:
Table 6: Summary of drug-drug interactions of BANZEL with other antiepileptic drugs
AED
Co-administered
Influence of Rufinamide on AED concentration a) Influence of AED on Rufinamide concentration
Carbamazepine Decrease by 7 to 13%b) Decrease by 19 to 26%
Dependent on dose of carbamazepine
Lamotrigine Decrease by 7 to 13%b) No Effect
Phenobarbital Increase by 8 to 13%b) Decrease by 25 to 46%c) d)
Independent of dose or concentration of phenobarbital
Phenytoin Increase by 7 to 21%b) Decrease by 25 to 46%c) d)
Independent of dose or concentration of phenytoin
Topiramate No Effect No Effect
Valproate No Effect Increase by <16 to 70%c)
Dependent on concentration of valproate
Primidone Not Investigated Decrease by 25 to 46%c) d)
Independent of dose or concentration of primidone
Benzodiazepines e) Not Investigated No Effect
a) Predictions are based on BANZEL concentrations at the maximum recommended dose of BANZEL.
b) Maximum changes predicted to be in pediatric patients and in adult patients who achieve significantly higher levels of BANZEL, as the effect of rufinamide on these AEDs is concentration-dependent.
c) Larger effects in pediatric patients at high doses/concentrations of AEDs.
d) Phenobarbital, primidone and phenytoin were treated as a single covariate (phenobarbital-type inducers) to examine the effect of these agents on BANZEL clearance.
e) All compounds of the benzodiazepine class were pooled to examine for ‘class effect’ on BANZEL clearance.


Table name:
Interacting Drug Interaction
Theophylline Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin Monitor phenytoin level (7)
Methotrexate Monitor for methotrexate toxicity (7)
Cyclosporine May increase serum creatinine. Monitor serum creatinine (7)
Multivalent cation-containing products including antacids, metal cations or didanosine Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin (7)


Table name:
Table 2. Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T4 and T3 serum transport - but FT4 concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors
(SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.Refer to PRECAUTIONS, Drug Interactions for information regarding table.
 albuterol,  famotidine  nizatidine
  systemic and inhaled  felodipine  norfloxacin
 amoxicillin  finasteride  ofloxacin
 ampicillin,  hydrocortisone  omeprazole
  with or without  isoflurane  prednisone, prednisolone
  sulbactam  isoniazid  ranitidine
 atenolol  isradipine  rifabutin
 azithromycin  influenza vaccine  roxithromycin
 caffeine,  ketoconazole  sorbitol
   dietary ingestion  lomefloxacin  (purgative doses do not
 cefaclor  mebendazole  inhibit theophylline
 co-trimoxazole  medroxyprogesterone  absorption)
 (trimethoprim and  methylprednisolone  sucralfate
  sulfamethoxazole)  metronidazole  terbutaline, systemic
 diltiazem  metoprolol  terfenadine
 dirithromycin  nadolol  tetracycline
 enflurane  nifedipine  tocainide


Table name: Drugs That Interfere with HemostasisClinical Impact:• Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.Intervention:Monitor patients with concomitant use of VOLTAREN® GEL with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].AspirinClinical Impact:Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].Intervention:Concomitant use of VOLTAREN® GEL and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. VOLTAREN® GEL is not a substitute for low dose aspirin for cardiovascular protection.ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-BlockersClinical Impact:• NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.Intervention:• During concomitant use of VOLTAREN® GEL and ACE-inhibitors, ARBs, or beta- blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of VOLTAREN® GEL and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.DiureticsClinical Impact:Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.Intervention:During concomitant use of VOLTAREN® GEL with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].DigoxinClinical Impact:The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.Intervention:During concomitant use of VOLTAREN® GEL and digoxin, monitor serum digoxin levels.LithiumClinical Impact:NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.During concomitant use of VOLTAREN® GEL and lithium, monitor patients for signs of lithium toxicity.MethotrexateClinical Impact:Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).Intervention:During concomitant use of VOLTAREN® GEL and methotrexate, monitor patients for methotrexate toxicity.CyclosporineClinical Impact:Concomitant use of VOLTAREN® GEL and cyclosporine may increase cyclosporine's nephrotoxicity.Intervention:During concomitant use of VOLTAREN® GEL and cyclosporine, monitor patients for signs of worsening renal function.NSAIDs and SalicylatesClinical Impact:Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].Intervention:The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended.PemetrexedClinical Impact:Concomitant use of VOLTAREN® GEL and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).Intervention:During concomitant use of VOLTAREN® GEL and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and Gl toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
 
 
   
 
 
 
 
 
 
   
 
 
         
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
Intervention:
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
     


Table name:
Digoxin concentrations increased greater than 50%
Digoxin Serum
Concentration
Increase

Digoxin AUC
Increase


Recommendations
Quinidine NA 54-83% Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring.
Ritonavir NA 86%
Digoxin concentrations increased less than 50%
Amiodarone 17% 40% Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15 to 30% or by modifying the dosing frequency and continue monitoring.
Propafenone 28% 29%
Quinine NA 34-38%
Spironolactone NA 44%
Verapamil NA 24%


Table name:
Antiretrovirals
        Clinical Impact: The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology (12.3)]. Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see Clinical Pharmacology (12.3)]. There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole.
        Intervention: Rilpivirine-containing products: Concomitant use with omeprazole is contraindicated [see Contraindications (4)].

Atazanavir: Avoid concomitant use with omeprazole. See prescribing information for atazanavir for dosing information.

Nelfinavir: Avoid concomitant use with omeprazole. See prescribing information for nelfinavir.

Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities.

Other antiretrovirals: See prescribing information for specific antiretroviral drugs.
Warfarin
Clinical Impact: Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
Intervention: Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range.
Methotrexate
Clinical Impact: Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions (5.11)].
Intervention: A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate.
CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam)
Clopidogrel
Clinical Impact: Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology (12.3)].

There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel.
Intervention: Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy [see Warnings and Precautions (5.6)].
Citalopram
Clinical Impact: Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology (12.3)].
Intervention: Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.
Cilostazol
Clinical Impact: Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology (12.3)].
Intervention: Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.
Phenytoin
Clinical Impact: Potential for increased exposure of phenytoin.
Intervention: Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin.
Diazepam
Clinical Impact: Increased exposure of diazepam [see Clinical Pharmacology (12.3)].
Intervention: Monitor patients for increased sedation and reduce the dose of diazepam as needed.
Digoxin
Clinical Impact: Potential for increased exposure of digoxin [see Clinical Pharmacology (12.3)].
Intervention: Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)
Clinical Impact: Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
     Intervention: Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF [see Clinical Pharmacology (12.3)].

See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact: Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated.
Amoxicillin also has drug interactions.
Intervention: See Contraindications, Warnings and Precautions in prescribing information for clarithromycin.

See Drug Interactions in prescribing information for amoxicillin.
Tacrolimus
Clinical Impact: Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.
Intervention: Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact: Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions (5.10), Clinical Pharmacology (12.2)].
  Intervention: Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
Interaction with Secretin Stimulation Test
Clinical Impact: Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention: Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology (12.2)].
False Positive Urine Tests for THC
Clinical Impact: There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.
Intervention: An alternative confirmatory method should be considered to verify positive results.
Other
Clinical Impact: There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram).
Intervention: Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole.


Table name:
Interacting Drug Interaction
   Multivalent cation-containing products
   including antacids, metal cations or didanosine
   Absorption of levofloxacin is decreased when the tablet
   formulation  is taken within 2 hours of this product. (2.4, 7.1)
   Warfarin
   Effect may be enhanced. Monitor prothrombin time,
   INR, watch for bleeding (7.2)
   Antidiabetic agents
   Carefully monitor blood glucose (5.11, 7.3)


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor
(boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) VIAGRA 50 mg (95% CI)
Supine 9.08 (5.48, 12.68)
Standing
11.62 (7.34, 15.90)


Table name:
Table 2: Clinically Significant Drug Interactions with Mefenamic Acid Drugs That Interfere with Hemostasis
 Drugs That Interfere with Hemostasis
 Clinical Impact:   • Mefenamic acid and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of mefenamic acid and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. 
 Intervention: Monitor patients with concomitant use of mefenamic acid with anticoagulants (e.g.,warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS ; Hematologic Toxicity ).
 Aspirin
 Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation ).
 Intervention: Concomitant use of mefenamic acid and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS ; Hematologic Toxicity ). Mefenamic acid is not a substitute for low dose aspirin for cardiovascular protection.
 ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
 Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
 Intervention: • During concomitant use of mefenamic acid and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.  • During concomitant use of mefenamic acid and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS ; Renal Toxicity and Hyperkalemia ). • When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
 Diuretics
 Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
 Intervention During concomitant use of mefenamic acid with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS ; Renal Toxicity and Hyperkalemia ).
 Digoxin
 Clinical Impact: The concomitant use of mefenamic acid with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
 Intervention: During concomitant use of mefenamic acid and digoxin, monitor serum digoxin levels.
 Lithium
 Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
 Intervention: During concomitant use of mefenamic acid and lithium, monitor patients for signs of lithium toxicity.
 Methotrexate
 Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
 Intervention: During concomitant use of mefenamic acid and methotrexate, monitor patients for methotrexate toxicity.
 Cyclosporine
 Clinical Impact: Concomitant use of mefenamic acid and cyclosporine may increase cyclosporine’s nephrotoxicity.
 Intervention: During concomitant use of mefenamic acid and cyclosporine, monitor patients for signs of worsening renal function.
 NSAIDs and Salicylates
 Clinical Impact: Concomitant use of mefenamic acid with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS ; Gastrointestinal Bleeding, Ulceration and Perforation ).
 Intervention: The concomitant use of mefenamic acid with other NSAIDs or salicylates is not recommended.
 Pemetrexed
 Clinical Impact: Concomitant use of mfenamic acid and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
 Intervention: During concomitant use of mefenamic acid and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.  NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
 Antacid
 Clinical Impact: In a single dose study (n= 6), ingestion of an antacid containing 1.7-gram of magnesium hydroxide with 500-mg of mefenamic acid increased the Cmax and AUC of mefenamic acid by 125% and 36%, respectively.
 Intervention: Concomitant use of mefenamic acid and antacids is not generally recommended because of possible increased adverse events.


Table name:
Factors Dosage Adjustments for Aripirazole Tablets
Known CYP2D6 Poor Metabolizers Administer half of usual dose
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors Administer half of usual dose
Strong CYP2D6 and CYP3A4 inhibitors Administer a quarter of usual dose
Strong CYP3A4 inducers Double usual dose over 1 to 2 weeks


Table name:
Table 18. Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered
Drug
Dosing Schedule Effect on Active Moiety
(Risperidone + 9-
Hydroxy-Risperidone
(RatioChange relative to reference)
Risperidone
Dose
Recommendation
Coadministered
Drug
Risperidone AUC Cmax
Enzyme
(CYP2D6)
Inhibitors
Fluoxetine 20 mg/day 2 or 3 mg
twice daily
1.4 1.5 Reevaluate
dosing. Do not
exceed 8 mg/day
Paroxetine 10 mg/day 4 mg/day 1.3 - Reevaluate
dosing. Do not
exceed 8 mg/day
20 mg/day 4 mg/day 1.6 -
40 mg/day 4 mg/day 1.8 -
Enzyme
(CYP3A/PgP
inducers)
Inducers
Carbamazepine 573 ± 168
mg/day
3 mg twice
daily
0.51 0.55 Titrate dose
upwards. Do not
exceed twice the
patient’s usual
dose
Enzyme
(CYP3A)
Inhibitors
Ranitidine 150 mg twice
daily
1 mg single
dose
1.2 1.4 Dose adjustment
not needed
Cimetidine 400 mg twice
daily
1 mg single
dose
1.1 1.3 Dose adjustment
not needed
Erythromycin 500 mg 4 times
daily
1 mg single
dose
1.1 0.94 Dose adjustment
not needed
Other Drugs
Amitriptyline 50 mg twice
daily
3 mg twice
daily
1.2 1.1 Dose adjustment
not needed


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
 Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration  Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
 Drugs that may alter T 4 and T 3 metabolism
 Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug Dosing Schedule Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio Change relative to reference) Risperidone Dose Recommendation
Coadministered Drug Risperidone AUC Cmax
Enzyme (CYP2D6) Inhibitors
Fluoxetine 20 mg/day 2 or 3 mg twice daily 1.4 1.5 Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine 10 mg/day 4 mg/day 1.3 - Re-evaluate dosing. Do not exceed 8 mg/day
20 mg/day 4 mg/day 1.6 -
40 mg/day 4 mg/day 1.8 -
Enzyme (CYP3A/PgP inducers) Inducers
Carbamazepine 573 ± 168 mg/day 3 mg twice daily 0.51 0.55 Titrate dose upwards. Do not exceed twice the patient's usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine 150 mg twice daily 1 mg single dose 1.2 1.4 Dose adjustment not needed
Cimetidine 400 mg twice daily 1 mg single dose 1.1 1.3 Dose adjustment not needed
Erythromycin 500 mg four times daily 1 mg single dose 1.1 0.94 Dose adjustment not needed
Other Drugs
Amitriptyline 50 mg twice daily 3 mg twice daily 1.2 1.1 Dose adjustment not needed


Table name:
Table 4: Clinically Relevant Interactions Affecting Omeprazole When Co-Administered with Other Drugs
CYP2C19 or CYP3A4 Inducers
Clinical Impact:
Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology ( 12.3)].
Intervention:
St. John’s Wort, rifampin: Avoid concomitant use with omeprazole [see Warnings and Precautions ( 5.9)].
Ritonavir-containing products: see prescribing information for specific drugs.
CYP2C19 or CYP3A4 Inhibitors
Clinical Impact:
Increased exposure of omeprazole [see Clinical Pharmacology ( 12.3)].
Intervention:
Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered.
 
See prescribing information for voriconazole.


Table name:
Table 4. Sevelamer Drug Interactions
Oral drugs for which sevelamer did not alter the pharmacokinetics when administered concomitantly
Digoxin
Enalapril
Iron
Metoprolol
Warfarin
Oral drugs that have demonstrated interaction with sevelamer and are to be dosed separately from Renagel
Dosing Recommendations
Ciprofloxacin Take at least 2 hours before or 6 hours after sevelamer
Mycophenolate mofetil Take at least 2 hours before sevelamer


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine Decreased lamotrigine levels approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? CBZ epoxide May increase CBZ epoxide levels.
Phenobarbital/Primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT) ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine Increased lamotrigine concentrations slightly more than 2 fold.
? valproate Decreased valproate concentrations an average of 25% over a 3 week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
 Table 7 Summary of AED Interactions with Oxcarbazepine
 AED Coadministered  Dose of AED (mg/day)  Oxcarbazepine Dose (mg/day)  Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval)  Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
 Carbamazepine  400 to 2000  900  nc1  40% decrease
[CI: 17% decrease, 57% decrease]
 Phenobarbital  100 to 150  600 to 1800  14% increase
[CI: 2% increase, 24% increase]
 25% decrease
[CI: 12% decrease, 51% decrease]
 Phenytoin  250 to 500  600 to 1800 >1200 to 2400  nc1,2
up to 40% increase3
[CI: 12% increase, 60% increase]
 30% decrease
[CI: 3% decrease, 48% decrease]
 Valproic acid  400 to 2800  600 to 1800  nc1  18% decrease
[CI: 13% decrease, 40% decrease]


Table name:
Inhibitors of CYP3A4
Clinical Impact: The concomitant use of fentanyl transdermal system and CYP3A4 inhibitors can increase the plasma concentration of fentanyl, resulting in increased or prolonged opioid effects particularly when an inhibitor is added after a stable dose of fentanyl transdermal system is achieved [see Warnings and Precautions (5.5)].

After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the fentanyl transdermal system plasma concentration will decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to fentanyl.
Intervention: If concomitant use is necessary, consider dosage reduction of fentanyl transdermal system until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals.

If a CYP3A4 inhibitor is discontinued, consider increasing the fentanyl transdermal system dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
Examples Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir), grape fruit juice
CYP3A4 Inducers
Clinical Impact: The concomitant use of fentanyl transdermal system and CYP3A4 inducers can decrease the plasma concentration of fentanyl [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to fentanyl [see Warnings and Precautions (5.5)].

After stopping a CYP3A4 inducer, as the effects of the inducer decline, the fentanyl plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.
Intervention: If concomitant use is necessary, consider increasing the fentanyl transdermal system dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider fentanyl transdermal system dosage reduction and monitor for signs of respiratory depression.
Examples: Rifampin, carbamazepine, phenytoin
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.7)].
Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Warnings and Precautions 5.10].
Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue fentanyl transdermal system if serotonin syndrome is suspected.
Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome [see Warnings and Precautions (5.10)] or opioid toxicity (e.g., respiratory depression, coma).
Intervention: The use of fentanyl transdermal system is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples: phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact: May reduce the analgesic effect of fentanyl transdermal system and/or precipitate withdrawal symptoms.
Intervention: Avoid concomitant use.
Examples: butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact: Fentanyl transdermal system may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of fentanyl transdermal system and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when fentanyl transdermal system is used concomitantly with anticholinergic drugs.


Table name:
Table 12: Effect of Voriconazole on Pharmacokinetics of Other Drugs
Drug/Drug Class
(Mechanism of Interaction by Voriconazole)
Drug Plasma Exposure
(Cmax and AUCτ)
Recommendations for Drug Dosage Adjustment/Comments
SirolimusResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects
(CYP3A4 Inhibition)
Significantly Increased Contraindicated
Rifabutin
(CYP3A4 Inhibition)
Significantly Increased Contraindicated
EfavirenzResults based on in vivo clinical study following repeat oral dosing with 400 mg Q12h for 1 day, then 200 mg Q12h for at least 2 days voriconazole to healthy subjects
(CYP3A4 Inhibition)
Significantly Increased When voriconazole is coadministered with efavirenz, voriconazole maintenance dose should be increased to 400 mg Q12h and efavirenz should be decreased to 300 mg Q24h (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION-Dosage Adjustment)
High-dose Ritonavir (400 mg Q12h)(CYP3A4 Inhibition) No Significant Effect of Voriconazole on Ritonavir Cmax or AUCτ Contraindicated because of significant reduction of voriconazole Cmax and AUCτ
Low-dose Ritonavir (100mg Q12h) Slight Decrease in Ritonavir Cmax and AUCτ Coadministration of voriconazole and low-dose ritonavir (100 mg Q12h) should be avoided (due to the reduction in voriconazole Cmax and AUCτ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine
(CYP3A4 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids
(CYP450 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Contraindicated
Cyclosporine
(CYP3A4 Inhibition)
AUCτ Significantly Increased; No Significant Effect on Cmax When initiating therapy with VFEND in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When VFEND is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
MethadoneResults based on in vivo clinical study following repeat oral dosing with 400 mg Q12h for 1 day, then 200 mg Q12h for 4 days voriconazole to subjects receiving a methadone maintenance dose (30–100 mg QD) (CYP3A4 Inhibition) Increased Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Alfentanil (CYP3A4 Inhibition) Significantly Increased Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with VFEND. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary (see CLINICAL PHARMACOLOGY - Drug Interactions).
Tacrolimus
(CYP3A4 Inhibition)
Significantly Increased When initiating therapy with VFEND in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When VFEND is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin
(CYP2C9 Inhibition)
Significantly Increased Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition) Increased Monitoring for adverse events related to oral contraceptives is recommended during coadministration.
Warfarin
(CYP2C9 Inhibition)
Prothrombin Time Significantly Increased Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed.
Omeprazole
(CYP2C19/3A4 Inhibition)
Significantly Increased When initiating therapy with VFEND in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors
(CYP3A4 Inhibition)
In Vivo Studies Showed No Significant Effects on Indinavir Exposure

In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism
(Increased Plasma Exposure)
No dosage adjustment for indinavir when coadministered with VFEND

Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors
(CYP3A4 Inhibition)
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs
(Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity related to NNRTI
Benzodiazepines
(CYP3A4 Inhibition)
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism
(Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.
HMG-CoA Reductase Inhibitors (Statins)
(CYP3A4 Inhibition)
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism
(Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers
(CYP3A4 Inhibition)
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism
(Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics
(CYP2C9 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids
(CYP3A4 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed.


Table name:
Concomitant Drug Name or Drug Class Clinical Rationale Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) The concomitant use of aripiprazole with strong CYP3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)] . With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)] .
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin) The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)] . With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)] .
Antihypertensive Drugs Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.7)] .
Benzodiazepines(e.g., lorazepam) The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.7)] . Monitor sedation and blood pressure. Adjust dose accordingly.


Table name:
Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol, famotidine nizatidine
systemic and inhaled felodipine norfloxacin
amoxicillin finasteride ofloxacin
ampicillin, hydrocortisone omeprazole
with or without isoflurane prednisone, prednisolone
sulbactam isoniazid ranitidine
atenolol isradipine rifabutin
azithromycin influenza vaccine roxithromycin
caffeine, ketoconazole sorbitol
  dietary ingestion lomefloxacin (purgative doses do not
cefaclor mebendazole inhibit theophylline
co-trimoxazole medroxyprogesterone absorption)
(trimethoprim and methylprednisolone sucralfate
sulfamethoxazole) metronidazole terbutaline, systemic
diltiazem metoprolol terfenadine
dirithromycin nadolol tetracycline
enflurane nifedipine tocainide


Table name:
Calcium Channel Blockers Antifungals Antibiotics Glucocorticoids Other Drugs
diltiazem fluconazole azithromycin methylprednisolone Allopurinol
nicardipine itraconazole clarithromycin   Amiodarone
verapamil ketoconazole erythromycin   Bromocriptine
  voriconazole quinupristin/
dalfopristin
  colchicine
        danazol
        imatinib
        metoclopramide
        nefazodone
        oral contraceptives


Table name:
Concomitant Drug Name or Drug Class Clinical Rationale Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) The concomitant use of aripiprazole with strong CYP3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)]. With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin) The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)]. With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Antihypertensive Drugs Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.7)].
Benzodiazepines(e.g., lorazepam) The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.7)]. Monitor sedation and blood pressure. Adjust dose accordingly.


Table name:
Summary of AED interactions with topiramate ( 7.1).
AED Co-administered AED Concentration Topiramate Concentration
Phenytoin NC or 25% increase a 48% decrease
Carbamazepine (CBZ) NC 40% decrease
CBZ epoxide b NC NE
Valproic acid 11% decrease 14% decrease
Phenobarbital NC NE
Primidone NC NE
Lamotrigine NC at TPM doses up to 400mg/day 13% decrease


Table name:
Table 5. Established and Other Potentially Significant Drug Interactions
↓= Decreased (induces lamotrigine glucuronidation).
↑= Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine ↓levonorgestrel Decreased lamotrigine concentrations approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine and Carbamazepine epoxide ↓ lamotrigine ? carbamazepine epoxide Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels.
Lopinavir/ritonavir ↓ lamotrigine Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir ↓ lamotrigine Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine ? valproate Increased lamotrigine concentrations slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.


Table name:
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
  Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. ( 2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose ( 5.12, 7.3)


Table name:
Table 2       Effects of Paroxetine on Other Drugs
Concomitant
Drug Name


Effect of Paroxetine on
Other Drugs
Clinical Recommendations
Thioridazine



Increased plasma concentrations of thioridazine

Potential QTc prolongation
Concomitant use of thioridazine and BRISDELLE is
contraindicated.
Pimozide



Increased plasma concentrations
of pimozide. Potential QTc
prolongation
Concomitant use of pimozide and BRISDELLE is
contraindicated.
Tamoxifen


Reduced plasma concentrations
of active tamoxifen metabolite
Consider avoiding concomitant use of tamoxifen
and BRISDELLE.

Tricyclic
Antidepressant
(TCA)
(e.g., Desipramine)

Increased plasma concentrations
and elimination half-life
Plasma TCA concentrations may need to be
monitored and the dose of TCA may need to be
reduced if a TCA is co-administered with
BRISDELLE. Monitor tolerability.
Risperidone



Increased plasma concentrations
of risperidone
A lower dosage of risperidone may be necessary
(see the Full Prescribing Information for
risperidone). Monitor tolerability.
Atomoxetine



Increased exposure of
atomoxetine
A lower dosage of atomoxetine may be necessary
(see Full Prescribing Information for atomoxetine).
Monitor tolerability.
Drugs Highly Bound
to Plasma Protein
(e.g., Warfarin)

Increased free plasma
concentrations
The dosage of warfarin may need to be reduced.
Monitor tolerability and the International
Normalized Ratio.
Digoxin


Decreased plasma concentrations
of digoxin
Dosage of digoxin may need to be increased.
Monitor digoxin concentrations and clinical effect.
Theophylline



Increased plasma concentrations
of theophylline
Dosage of theophylline may need to be decreased.
Monitor theophylline concentrations and
tolerability.


Table name:
Bleeding times
Clinical Impact: Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention: This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact: The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention: Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact: Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention: This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.


Table name:
Table 7 Summary of AED Interactions with Oxcarbazepine
AED Coadministered Dose of AED (mg/day) Oxcarbazepine Dose (mg/day) Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval) Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine 400-2000 900 nc nc denotes a mean change of less than 10% 40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital 100-150 600-1800 14% increase [CI: 2% increase, 24% increase] 25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin 250-500 600-1800 >1200-2400 nc Pediatrics up to 40% increase [CI: 12% increase, Mean increase in adults at high oxcarbazepine doses 60% increase] 30% decrease [CI: 3% decrease, 48% decrease]
Valproic acid 400-2800 600-1800 nc 18% decrease [CI: 13% decrease, 40% decrease]


Table name:
Table 3:   Drugs that Can Increase the Risk of Bleeding
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 45.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents Prescribing Recommendations
   Itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine, danazol    Contraindicated with simvastatin
   Amiodarone, verapamil, diltiazem    Do not exceed 10 mg simvastatin daily
   Amlodipine, ranolazine    Do not exceed 20 mg simvastatin daily
   Grapefruit juice    Avoid large quantities of grapefruit juice (>1 quart daily) 


Table name:
 Interacting Agents  Prescribing Recommendations 
 Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, Posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine,danazol  Contraindicated with simvastatin 
 Verapamil, diltiazem  Do not exceed 10 mg simvastatin daily
 Amiodarone, amlodipine, ranolazine   Do not exceed 20 mg simvastatin daily
 Grapefruit juice  Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
* For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Interacting Agents
Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol
Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone
Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine
Do not exceed 20 mg simvastatin daily
Lomitapide
For patients with HoFH, do not exceed 20 mg simvastatin daily*
Grapefruit juice
Avoid grapefruit juice


Table name:
Table II. Clinically significant drug interactions with theophylline.Refer to PRECAUTIONS, Drug Interactions for further information regarding table.
Drug Type of Interaction EffectAverage effect on steady-state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.
Adenosine Theophylline blocks adenosine receptors. Higher doses of adenosine may be required to achieve desired effect.
Alcohol A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours. 30% increase
Allopurinol Decreases theophylline clearance at allopurinol doses ≥600 mg/day. 25% increase
Aminoglutethimide Increases theophylline clearance by induction of microsomal enzyme activity. 25% decrease
Carbamazepine Similar to aminoglutethimide. 30% decrease
Cimetidine Decreases theophylline clearance by inhibiting cytochrome P450 1A2. 70% increase
Ciprofloxacin Similar to cimetidine. 40% increase
Clarithromycin Similar to erythromycin. 25% increase
Diazepam Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram Decreases theophylline clearance by inhibiting hydroxylation and demethylation. 50% increase
Enoxacin Similar to cimetidine. 300% increase
Ephedrine Synergistic CNS effects Increased frequency of nausea, nervousness, and insomnia.
Erythromycin Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3. 35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown. 30% increase
Flurazepam Similar to diazepam. Similar to diazepam.
Fluvoxamine Similar to cimetidine. Similar to cimetidine.
Halothane Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines. Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-A Decreases theophylline clearance. 100% increase
Isoproterenol (IV) Increase theophylline clearance. 20% increase
Ketamine Pharmacologic May lower theophylline seizure threshold.
Lithium Theophylline increases renal lithium clearance. Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam Similar to diazepam. Similar to diazepam.
Methotrexate (MTX) Decreases theophylline clearance. 20% increase after low dose MTX, higher dose MTX may have a greater effect.
Mexiletine Similar to disulfiram. 80% increase
Midazolam Similar to diazepam. Similar to diazepam.
Moricizine Increases theophylline clearance. 25% decrease
Pancuronium Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition. Larger dose of pancuronium may be required to achieve neuromuscular blockade.
Pentoxifylline Decreases theophylline clearance. 30% increase
Phenobarbital (PB) Similar to aminoglutethimide. 25% decrease after two weeks of concurrent PB.
Phenytoin Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption. Serum theophylline and phenytoin concentrations decrease about 40%.
Propafenone Decreases theophylline clearance and pharmacologic interaction. 40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Propranolol Similar to cimetidine and pharmacologic interaction. 100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Rifampin Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity. 20 to 40% decrease
Sulfinpyrazone Increase theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline. 20% increase
Tacrine Similar to cimetidine, also increases renal clearance of theophylline. 90% increase
Thiabendazole Decreases theophylline clearance. 190% increase
Ticlopidine Decreases theophylline clearance. 60% increase
Troleandomycin Similar to erythromycin. 33 to 100% increase depending on troleandomycin dose.
Verapamil Similar to disulfiram. 20% increase


Table name:
Figure 2: Effect of venlafaxine on the pharmacokinetics interacting drugs and their active metabolites.


Table name:
Table 18. Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
*Change relative to reference
Coadministered Drug
 
Dosing Schedule
Effect on Active Moiety
(Risperidone + 9- Hydroxy-
Risperidone (Ratio*)
Risperidone Dose
Recommendation
Coadministered Drug
Risperidone
AUC
Cmax
Enzyme (CYP2D6) inhibitors
 
 
 
 
Fluoxetine
20 mg/day
2 or 3 mg twice daily
1.4
1.5

Re-evaluate dosing.
Do not exceed 8 mg/day
Paroxetine
10 mg/day
4 mg/day
1.3
-

Re-evaluate dosing.
Do not exceed 8 mg/day
20 mg/day
4 mg/day
1.6
-
40 mg/day
4 mg/day
1.8
-
Enzyme (CYP3A/ PgP inducers) Inducers
 
 
 
 
 
Carbamazepine
573 ± 168 mg/day
 
3 mg twice daily
 
0.51
 
0.55
 

Titrate dose upwards.
Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) inhibitors
 
 
 
 
 
Ranitidine
150 mg twice daily
1 mg single dose
1.2
1.4
Dose adjustment not needed
Cimetidine
400 mg twice daily
1 mg single dose
1.1
1.3
Dose adjustment not needed
Erythromycin
500 mg four times daily
1 mg single dose
1.1
0.94
Dose adjustment not needed
Other Drugs
 
 
 
 
 
Amitriptyline
50 mg twice daily
3 mg twice daily
1.2
1.1
Dose adjustment not Needed


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T 4 and T 3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin/Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens/Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non-Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT 4 . Continued administration results in a decrease in serum T 4 and normal FT 4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T 4 and T 3 to TBG and transthyretin. An initial increase in serum FT 4 is followed by return of FT 4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T 4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T 4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ³ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T 4 to T 3, leading to decreased T 3 levels. However, serum T 4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T 3 and T 4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T 3 concentrations by 30% with minimal change in serum T 4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T 3 and T 4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias
and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123 I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 18Summary of Effect of Coadministered Drugs on Exposure to Active Moiety(Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients withSchizophrenia
*Change relative to reference
Coadministered Drug
Dosing Schedule

Effect on Active
Moiety
(Risperidone + 9-
Hydroxy-
Risperidone (Ratio*)

Risperidone Dose
Recommendation

Coadministered Drug
Risperidone
AUC
Cm a x

Enzyme (CYP2D6) 
Inhibitors 





Fluoxetine 
20 mg/day
2 or 3 mg twice
daily
1.4
1.5
Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine 
10 mg/day
4 mg/day
1.3
-
Re-evaluate dosing. 

20 mg/day
4 mg/day
1.6
-
Do not exceed 8 mg/day

40 mg/day
4 mg/day
1.8
-

Enzyme (CYP3A/ 
PgP inducers) 





Carbamazepine 
573 ± 168 mg/day
3 mg twice daily
0.51
0.55
Titrate dose upwards.
Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) 
Inhibitors 





Ranitidine 
150 mg twice daily
1 mg single dose
1.2
1.4
Dose adjustment not
needed
Cimetidine 
400 mg twice daily
1 mg single dose
1.1
1.3
Dose adjustment not
needed
Erythromycin 
500 mg four times
daily
1 mg single dose
1.1
0.94
Dose adjustment not
needed
Other Drugs 





Amitriptyline 
50 mg twice daily
3 mg twice daily
1.2
1.1
Dose adjustment not
needed


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
↓= Decreased (induces lamotrigine glucuronidation).
↑= Increased (inhibits lamotrigine glucuronidation).
?= Conflicting data.
Concomitant  Drug
Effect  on  Concentration  of  Lamotrigine  or  Concomitant  Drug
Clinical  Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 
150 mcg levonorgestrel 
↓ lamotrigine 
↓ levonorgestrel 
Decreased lamotrigine concentrations approximately 50%. 
Decrease in levonorgestrel component by 19%. 
Carbamazepine and carbamazepine epoxide 
↓ lamotrigine 
? carbamazepine epoxide 
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. 
May increase carbamazepine epoxide levels. 
Lopinavir/ritonavir
↓ lamotrigine 

Decreased lamotrigine concentration approximately 50%. 

Atazanavir/ritonavir
↓ lamotrigine 

Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone
↓ lamotrigine
Decreased lamotrigine concentration approximately 40%.
Phenytoin
↓ lamotrigine
Decreased lamotrigine concentration approximately 40%.
Rifampin
↓ lamotrigine
Decreased lamotrigine AUC approximately 40%.
Valproate
↑ lamotrigine  
? valproate




Increased lamotrigine concentrations slightly more than 2-fold. 
There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.


Table name:
Effects on Steady-State Fexofenadine Pharmacokinetics After 7 Days of Co-Administration with Fexofenadine Hydrochloride 120 mg Every 12 Hours (two times the recommended twice daily dose) in Healthy Volunteers (n=24)
Concomitant Drug Cmax SS
(Peak plasma concentration)
AUCSS(0–12h)
(Extent of systemic exposure)
Erythromycin
(500 mg every 8 hrs)
+82% +109%
Ketoconazole
(400 mg once daily)
+135% +164%


Table name:
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:

Table 1 Oral drugs that can be administered concomitantly with Velphoro

Calcitriol
Ciprofloxacin
Digoxin
Enalapril
Furosemide
HMG-CoA reductase inhibitors
Hydrochlorothiazide
Losartan
Metoprolol
Nifedipine
Omeprazole
Quinidine
Warfarin

Oral drugs that are to be separated from Velphoro and meals

  Dosing Recommendations
Doxycycline Take at least 1 hour before Velphoro.

Oral drugs that should not be prescribed with Velphoro

Levothyroxine


Table name:
Interacting DrugInteracting Drug InteractionInteraction
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products ( 2.4, 7.1)
Warfarin
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( 7.2)
Antidiabetic agents
Carefully monitor blood glucose ( 5.12, 7.3)


Table name:
Drugs that Affect Renal Function A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDS], COX-2 inhibitors may impair the excretion of digoxin.
Antiarrthymics Dofetilide Concomitant administration with digoxin was associated with a higher rate of torsades de pointes
Sotalol Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
Dronedarone Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone Analog Teriparatide Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement Thyroid Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics Epinephrine
Norepinephrine     
Dopamine
Can increase the risk of cardiac arrhythmias
Neuromuscular Blocking Agents      Succinylcholine May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.
Supplements Calcium If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.


Table name:
Table 2. Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T4 and T3 serum transport - but FT4 concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors
(SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Interacting DrugInteracting Drug InteractionInteraction
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products.
Warfarin
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( 7.2)
Antidiabetic agents
Carefully monitor blood glucose ( 5.11, 7.3)


Table name:
Table 1: Clinically Significant Drug Interactions with Morphine Sulfate Injection
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.4)].
Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Morphine Sulfate Injection if serotonin syndrome is suspected.
Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.7)].
Intervention: Do not use Morphine Sulfate Injection in patients taking MAOIs or within 14 days of stopping such treatment.
If urgent use of an opioid is necessary, use test doses and frequent titration of small doses of other opioids (such as oxycodone, hydrocodone, oxymorphone, hydrocodone, or buprenorphine) to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
Examples: phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact: May reduce the analgesic effect of Morphine Sulfate Injection and/or precipitate withdrawal symptoms.
Intervention: Avoid concomitant use.
Examples: butorphanol, nalbuphine, pentazocine, buprenorphine.


Table name:
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
Inhibitors of CYP2D6
Clinical Impact:
The concomitant use of tramadol hydrochloride and acetaminophen and CYP2D6 inhibitors may result in an increase in the plasma concentration of tramadol and a decrease in the plasma concentration of M1, particularly when an inhibitor is added after a stable dose of tramadol hydrochloride and acetaminophen is achieved. Since M1 is a more potent µ-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome.
 
After stopping a CYP2D6 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease and the M1 plasma concentration will increase which could increase or prolong therapeutic effects but also increase adverse reactions related to opioid toxicity, and may cause potentially fatal respiratory depression [see Clinical Pharmacology ( 12.3)] .
Intervention:
If concomitant use of a CYP2D6 inhibitor is necessary, follow patients closely for adverse reactions including opioid withdrawal, seizures and serotonin syndrome.
 
If a CYP2D6 inhibitor is discontinued, consider lowering tramadol hydrochloride and acetaminophen  dosage until stable drug effects are achieved. Follow patients closely for adverse events including respiratory depression and sedation.
Examples
Quinidine, fluoxetine, paroxetine and bupropion
Inhibitors of CYP3A4
Clinical Impact:
The concomitant use of tramadol hydrochloride and acetaminophen and CYP3A4 inhibitors can increase the plasma concentration of tramadol and may result in a greater amount of metabolism via CYP2D6 and greater levels of M1. Follow patients closely for increased risk of serious adverse events including seizures and serotonin syndrome, and adverse reactions related to opioid toxicity including potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of tramadol hydrochloride and acetaminophen is achieved.
 
After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease [see Clinical Pharmacology ( 12.3)] , resulting in decreased opioid efficacy and possibly signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol.
Intervention:
If concomitant use is necessary, consider dosage reduction of tramadol hydrochloride and acetaminophen until stable drug effects are achieved. Follow patients closely for seizures and serotonin syndrome, and signs of respiratory depression and sedation at frequent intervals.
 
If a CYP3A4 inhibitor is discontinued, consider increasing the tramadol hydrochloride and acetaminophen dosage until stable drug effects are achieved and follow patients for signs and symptoms of opioid withdrawal.
Examples
Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)
CYP3A4 Inducers
Clinical Impact:
The concomitant use of tramadol hydrochloride and acetaminophen and CYP3A4 inducers can decrease the plasma concentration of tramadol [see Clinical Pharmacology ( 12.3)] , resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to tramadol.
 
After stopping a CYP3A4 inducer, as the effects of the inducer decline, the tramadol plasma concentration will increase [see Clinical Pharmacology ( 12.3)] , which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression, seizures and serotonin syndrome.
Intervention:
If concomitant use is necessary, consider increasing the tramadol hydrochloride and acetaminophen dosage until stable drug effects are achieved. Follow patients for signs of opioid withdrawal.
 
If a CYP3A4 inducer is discontinued, consider tramadol hydrochloride and acetaminophen dosage reduction and monitor for seizures and serotonin syndrome, and signs of sedation and respiratory depression.
 
Patients taking carbamazepine, a CYP3A4 inducer, may have a significantly reduced analgesic effect of tramadol. Because carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of tramadol hydrochloride and acetaminophen and carbamazepine is not recommended.
Examples:
Rifampin, carbamazepine, phenytoin
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact:
Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:
Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions ( 5.6)].
Examples:
Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact:
The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention:
If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue tramadol hydrochloride and acetaminophen if serotonin syndrome is suspected.
Examples:
Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:
MAOI interactions with opioids may manifest as serotonin syndrome [see Warnings and Precautions ( 5.7)] or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions ( 5.2)] .
Intervention:
Do not use tramadol hydrochloride and acetaminophen in patients taking MAOIs or within 14 days of stopping such treatment.
Examples:
phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:
May reduce the analgesic effect of tramadol hydrochloride and acetaminophen and/or precipitate withdrawal symptoms.
Intervention:
Avoid concomitant use.
Examples:
butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact:
Tramadol may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:
Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of tramadol hydrochloride and acetaminophen and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact:
Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:
Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:
The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:
Monitor patients for signs of urinary retention or reduced gastric motility when tramadol hydrochloride and acetaminophen is used concomitantly with anticholinergic drugs.
Digoxin
Clinical Impact:
Post-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity.
Intervention:
Follow patients for signs of digoxin toxicity and adjust dosage of digoxin as needed.
Warfarin
Clinical Impact:
Post-marketing surveillance of tramadol has revealed rare reports of alteration of warfarin effect, including elevation of prothrombin times.
Intervention:
Monitor the prothrombin time of patients on warfarin for signs of an interaction and adjust the dosage of warfarin as needed.


Table name:
Table 4. The Effect of CRESEMBA on the Pharmacokinetics of Other Drugs
a 400 mg of lopinavir in combination with 100 mg of ritonavir.
Recommendation Comments
Lopinavir/ritonavira Use with Caution Concomitant administration of lopinavir/ritonavir and CRESEMBA resulted in decreased exposure of lopinavir and ritonavir that could possibly result in loss of antiviral efficacy [see Clinical Pharmacology (12.3)].
Atorvastatin Use with Caution Caution should be used when atorvastatin is used with CRESEMBA due to a potential increase in atorvastatin exposure. Monitor patients for adverse reactions that are typical of atorvastatin.
Cyclosporine Use with Caution Concomitant administration of CRESEMBA and cyclosporine results in increase in cyclosporine exposure. Monitor drug concentrations of cyclosporine and adjust dose as needed
[see Clinical Pharmacology (12.3)].
Sirolimus Use with Caution Concomitant administration of CRESEMBA and sirolimus results in increase in sirolimus exposure. Monitor drug concentrations of sirolimus and adjust dose as needed
[see Clinical Pharmacology (12.3)].
Tacrolimus Use with Caution Concomitant administration of CRESEMBA and tacrolimus results in increase in tacrolimus exposure. Monitor drug concentrations of tacrolimus and adjust dose as needed
[see Clinical Pharmacology (12.3)].
Midazolam Use with Caution Concomitant administration of CRESEMBA and midazolam results in increase in midazolam exposure. Consider dose reduction of midazolam when isavuconazole is coadministered [see Clinical Pharmacology (12.3)].
Bupropion Use with Caution Concomitant administration of CRESEMBA and bupropion results in decrease in bupropion exposure. Dose increase of bupropion may be necessary when coadministered with CRESEMBA, but should not exceed the maximum recommended dose [see Clinical Pharmacology (12.3)].
Mycophenolate Mofetil Use with Caution Concomitant administration of CRESEMBA and MMF results in increase in MMF exposure. Patients receiving CRESEMBA concurrently with MMF should be monitored for MPA-related toxicities [see Clinical Pharmacology (12.3)].
Digoxin Use with Caution Concomitant administration of CRESEMBA and digoxin results in increase in digoxin exposure. Serum digoxin concentrations should be monitored and used for titration when dosed concurrently with CRESEMBA
[see Clinical Pharmacology (12.3)].


Table name:
Table 3 Clinically Significant Drug Interactions with Meloxicam
Drugs that Interfere with Hemostasis
Clinical Impact:

Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:

Monitor patients with concomitant use of MOBIC with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact:

Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].
Intervention:

Concomitant use of MOBIC and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)].

MOBIC is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, or Beta-Blockers
Clinical Impact:

NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:

During concomitant use of MOBIC and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of MOBIC and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:

Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam.
Intervention:

During concomitant use of MOBIC with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Lithium
Clinical Impact:

NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [see Clinical Pharmacology (12.3)].
Intervention:

During concomitant use of MOBIC and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:

Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:

During concomitant use of MOBIC and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:

Concomitant use of MOBIC and cyclosporine may increase cyclosporine's nephrotoxicity.
Intervention:

During concomitant use of MOBIC and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:

Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention:

The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:

Concomitant use of MOBIC and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:

During concomitant use of MOBIC and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.

Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.

In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir ) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme
Inhibitors
Inducers
CYP2C9 
amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast
aprepitant, bosentan, carbamazepine, phenobarbital, rifampin 
CYP1A2 
acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton
montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking 
CYP3A4 
alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton
armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide 


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.11, 7.3)


Table name:
Table 2. Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T4 and T3 serum transport - but FT4 concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors
(SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
  Interacting Drug   Interaction
  Theophylline   Serious and fatal reactions. Avoid concomitant
use. Monitor serum level (7)
  Warfarin   Anticoagulant effect enhanced. Monitor
prothrombin time, INR, and bleeding (7)
  Antidiabetic agents   Hypoglycemia including fatal outcomes have been
reported. Monitor blood glucose (7)
  Phenytoin   Monitor phenytoin level (7)
  Methotrexate   Monitor for methotrexate toxicity (7)
  Cyclosporine   May increase serum creatinine. Monitor serum
creatinine (7)
  Multivalent cation-containing
products including antacids, metal cations or didanosine
  Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin (7)


Table name:
Table 5. Clinically-Significant Drug Interactions with Sertraline Hydrochloride
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:
The concomitant use of SSRIs including sertraline hydrochloride and MAOIs increases the risk of serotonin syndrome.
Intervention:
Sertraline hydrochloride is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [See Dosage and Administration (2.5), Contraindications (4), Warnings and Precautions (5.2)].
Examples:
selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue
Pimozide
Clinical Impact:
Increased plasma concentrations of pimozide, a drug with a narrow therapeutic index, may increase the risk of QT prolongation and ventricular arrhythmias.
Intervention:
Concomitant use of pimozide and sertraline hydrochloride is contraindicated [See Contraindications (4)].
Other Serotonergic Drugs
Clinical Impact:
The concomitant use of serotonergic drugs with sertraline hydrochloride increases the risk of serotonin syndrome.
Intervention:
Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of sertraline hydrochloride and/or concomitant serotonergic drugs [See Warnings and Precautions (5.2)].
Examples:
other SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort
Drugs that Interfere with Hemostasis (antiplatelet agents and anticoagulants)
Clinical Impact:
The concurrent use of an antiplatelet agent or anticoagulant with sertraline hydrochloride may potentiate the risk of bleeding.
Intervention:
Inform patients of the increased risk of bleeding associated with the concomitant use of sertraline hydrochloride and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio [See Warnings and Precautions (5.3)].
Examples:
aspirin, clopidogrel, heparin, warfarin
Drugs Highly Bound to Plasma Protein
Clinical Impact:
Sertraline hydrochloride is highly bound to plasma protein. The concomitant use of sertraline hydrochloride with another drug that is highly bound to plasma protein may increase free concentrations of sertraline hydrochloride or other tightly-bound drugs in plasma [See Clinical Pharmacology (12.3)].
Intervention:
Monitor for adverse reactions and reduce dosage of sertraline hydrochloride or other protein-bound drugs as warranted.
Examples:
warfarin
Drugs Metabolized by CYP2D6
Clinical Impact:
Sertraline hydrochloride is a CYP2D6 inhibitor [See Clinical Pharmacology (12.3)]. The concomitant use of sertraline hydrochloride with a CYP2D6 substrate may increase the exposure of the CYP2D6 substrate.
Intervention:
Decrease the dosage of a CYP2D6 substrate if needed with concomitant sertraline hydrochloride use. Conversely, an increase in dosage of a CYP2D6 substrate may be needed if sertraline hydrochloride is discontinued.
Examples:
propafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, thoridazine, tolterodine, venlafaxine
Phenytoin
Clinical Impact:
Phenytoin is a narrow therapeutic index drug. Sertraline hydrochloride may increase phenytoin concentrations.
Intervention:
Monitor phenytoin levels when initiating or titrating sertraline hydrochloride. Reduce phenytoin dosage if needed.
Examples:
phenytoin, fosphenytoin


Table name:
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Grapefruit juice Avoid grapefruit juice


Table name:
Table 4   Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table 5 for Magnitude of Interaction.
Drug Name
Effect on Concentration of Nevirapine or Concomitant Drug
Clinical Comment
HIV Antiviral Agents: Protease Inhibitors (PIs)
Atazanavir/Ritonavir*
↓ Atazanavir
 
↑ Nevirapine
Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures.
Fosamprenavir*
 
 
 
Fosamprenavir/Ritonavir*
 
↓Amprenavir
↑Nevirapine
 
 
↓Amprenavir
↑Nevirapine
 
Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.
 
No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied.
Indinavir*
 
↓ Indinavir
 
The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established.
Lopinavir/Ritonavir*
 
↓ Lopinavir
 
Dosing in adult patients:
 
A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.
 
Dosing in pediatric patients:
 
Please refer to the Kaletra® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.
Nelfinavir*
↓Nelfinavir M8 Metabolite
↓Nelfinavir Cmin
The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established.
Saquinavir/ritonavir
The interaction between nevirapine and saquinavir/ritonavir has not been evaluated
The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz*
 
 
Delavirdine
Etravirine
Rilpivirine
↓Efavirenz
The appropriate doses of these combinations with respect to safety and efficacy have not been established.
 
Plasma concentrations may be altered.
Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial.
Hepatitis C Antiviral Agents
 
 
Boceprevir
 
 
 
Plasma concentrations of boceprevir may be decreased due to induction of CYP3A4/5 by nevirapine.
Nevirapine and boceprevir should not be coadministered because decreases in boceprevir plasma concentrations may result in a reduction in efficacy.
 
 
Telaprevir
 
Plasma concentrations of telaprevir may be decreased due to induction of CYP3A4 by nevirapine and plasma concentrations of nevirapine may be increased due to inhibition of CYP3A4 by telaprevir.
 
 
Nevirapine and telaprevir should not be coadministered because changes in plasma concentrations of nevirapine, telaprevir, or both may result in a reduction in telaprevir efficacy or an increase in nevirapine-associated adverse events.
 
 
Other Agents
Analgesics:
Methadone*
↓Methadone
Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Antiarrhythmics:
Amiodarone, disopyramide, lidocaine
Plasma concentrations may be decreased.
Appropriate doses for this combination have not been established.
Antibiotics:
Clarithromycin*
 
 
 
 
 
 
 
 
Rifabutin*
 
 
 
 
 
 
 
Rifampin*
↓Clarithromycin
↑14-OH clarithromycin
 
 
 
 
 
 
 
 
↑Rifabutin
 
 
 
 
 
 
 
↓ Nevirapine
Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium­intracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.
 
Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.
 
Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Anticonvulsants:
Carbamazepine, clonazepam, ethosuximide
 
Plasma concentrations of nevirapine and the anticonvulsant may be decreased.
 
Use with caution and monitor virologic response and levels of anticonvulsants.
 
Antifungals:
Fluconazole*
 
 
 
 
 
Ketoconazole*
 
 
 
 
Itraconazole
 
↑Nevirapine
 
 
 
 
 
↓ Ketoconazole
 
 
 
 
↓ Itraconazole
Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events.
 
 
Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.
 
Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug.
Antithrombotics:
Warfarin
 
Plasma concentrations may be increased.
 
Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.
 
Calcium channel blockers:
Diltiazem, nifedipine, verapamil
 
Plasma concentrations may be decreased.
 
Appropriate doses for these combinations have not been established.
 
Cancer chemotherapy:
Cyclophosphamide
 
Plasma concentrations may be decreased.
 
Appropriate doses for this combination have not been established.
 
Ergot alkaloids:
Ergotamine
 
Plasma concentrations may be decreased.
 
Appropriate doses for this combination have not been established.
 
Immunosuppressants: Cyclosporine, tacrolimus, sirolimus
Plasma concentrations may be decreased.
 
Appropriate doses for these combinations have not been established.
 
Motility agents:
Cisapride
 
Plasma concentrations may be decreased.
 
Appropriate doses for this combination have not been established.
 
Opiate agonists:
Fentanyl
 
Plasma concentrations may be decreased.
 
Appropriate doses for this combination have not been established.
 
Oral contraceptives:
Ethinyl estradiol and Norethindrone*
 
↓ Ethinyl estradiol
↓ Norethindrone
 
Despite lower ethinyl estradiol and norethindrone exposures when coadministered with nevirapine, literature reports suggest that nevirapine has no effect on pregnancy rates among HIV-infected women on combined oral contraceptives. When coadministered with nevirapine, no dose adjustment of ethinyl estradiol or norethindrone is needed when used in combination for contraception.
 
When these oral contraceptives are used for hormonal regulation during nevirapine therapy, the therapeutic effect of the hormonal therapy should be monitored.
* The interaction between nevirapine and the drug was evaluated in a clinical study. All other drug interactions shown are predicted.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7.1, 7.2, 7.3, 7.4)
Interacting Agents Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone Avoid simvastatin
Gemfibrozil, cyclosporine, danazol Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil Do not exceed 20 mg simvastatin daily
Diltiazem Do not exceed 40 mg simvastatin daily
Grapefruit juice Avoid large quantities of grapefruit juice (> 1 quart daily)


Table name:
 Drugs That Interfere with  Hemostasis
Clinical  Impact:  •  Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of Celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.
•  Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
 Intervention:  Monitor patients with concomitant use of celecoxib with anticoagulants (e.g., warfarin), antiplatelet  agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine  reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions  (5.11)].
 Aspirin
 Clinical  Impact:  Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin  does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the  concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse  reactions as compared to use of the NSAID alone [see Warnings and Precautions  (5.2)].
 In two studies in healthy volunteers, and in patients with osteoarthritis and established heart  disease respectively, celecoxib (200 to 400 mg daily) has demonstrated a lack of interference with the  cardioprotective antiplatelet effect of aspirin (100 to 325  mg).
 Intervention:  Concomitant use of celecoxib and analgesic doses of aspirin is not generally recommended because of  the increased risk of bleeding [see Warnings and Precautions  (5.11)].
Celecoxib is not a substitute for low dose aspirin for cardiovascular  protection.
 ACE  Inhibitors,  Angiotensin  Receptor  Blockers,  and  Beta-Blockers
 Clinical  Impact:  •  NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).
•  In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
 Intervention:  •  During concomitant use of celecoxib and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.
•  During concomitant use of celecoxib and ACE-inhibitors or ARBs in patients who are elderly, volume- depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)].
•  When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
 Diuretics
 Clinical  Impact:  Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect  of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to  the NSAID inhibition of renal prostaglandin  synthesis.
 Intervention:  During concomitant use of celecoxib with diuretics, observe patients for signs of worsening renal  function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and  Precautions (5.6)].
 Digoxin
 Clinical  Impact:  The concomitant use of Celecoxib with digoxin has been reported to increase the serum concentration  and prolong the half-life of  digoxin.
 Intervention:  During concomitant use of celecoxib and digoxin, monitor serum digoxin  levels.
 Lithium
 Clinical  Impact:  NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance.  The mean minimum lithium concentration increased 15%, and the renal clearance decreased by  approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin  synthesis.
Intervention:  During concomitant use of celecoxib and lithium, monitor patients for signs of lithium  toxicity.
 Methotrexate
 Clinical  Impact:  Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity  (e.g., neutropenia, thrombocytopenia, renal  dysfunction).
 Celecoxib has no effect on methotrexate  pharmacokinetics.
 Intervention:  During concomitant use of celecoxib and methotrexate, monitor patients for methotrexate  toxicity.
 Cyclosporine
 Clinical  Impact:  Concomitant use of celecoxib and cyclosporine may increase cyclosporine’s  nephrotoxicity.
 Intervention:  During concomitant use of celecoxib and cyclosporine, monitor patients for signs of worsening  renal function.
 NSAIDs and  Salicylates
 Clinical  Impact:  Concomitant use of Celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk  of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions  (5.2)].
 Intervention:  The concomitant use of Celecoxib with other NSAIDs or salicylates is not  recommended.
 Pemetrexed
 Clinical  Impact:  Concomitant use of celecoxib and pemetrexed may increase the risk of  pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing  information).
 Intervention:  During concomitant use of celecoxib and pemetrexed, in patients with renal impairment whose  creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI  toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of  two days before, the day of, and two days following administration of  pemetrexed. 
In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer  half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five  days before, the day of, and two days following pemetrexed  administration.
 CYP2C9 Inhibitors or  inducers
  Clinical  Impact:  Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver.  Co­administration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may  enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g.  rifampin) may lead to compromised efficacy of  celecoxib.
 Intervention:  Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A  dosage adjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers.  [see Clinical Pharmacology  (12.3)].
 CYP2D6  substrates
 Clinical  Impact:  In vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6.  Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6  (e.g. atomoxetine), and celecoxib may enhance the exposure and toxicity of these  drugs.
  Intervention:  Evaluate each patient’s medical history when consideration is given to prescribing celecoxib. A  dosage adjustment may be warranted when celecoxib is administered with CYP2D6  substrates. [see Clinical Pharmacology  (12.3)].
 Corticosteroids
 Clinical  Impact:  Concomitant use of corticosteroids with celecoxib may increase the risk of GI ulceration or  bleeding.
 Intervention:  Monitor patients with concomitant use of celecoxib with corticosteroids for signs of bleeding  [see Warnings and Precautions  (5.2)].


Table name:
Table 3 Includes clinically significant drug interactions with buprenorphine and naloxone sublingual tablets
Benzodiazepines
Clinical Impact:
There have been a number of reports regarding coma and death associated with the misuse and abuse of the combination of buprenorphine and benzodiazepines. In many, but not all of these cases, buprenorphine was misused by self-injection of crushed buprenorphine tablets. Preclinical studies have shown that the combination of benzodiazepines and buprenorphine altered the usual ceiling effect on buprenorphine-induced respiratory depression, making the respiratory effects of buprenorphine appear similar to those of full opioid agonists.
Intervention:
Closely monitor patients with concurrent use of buprenorphine and naloxone sublingual tablets and benzodiazepines. Warn patients that it is extremely dangerous to self-administer benzodiazepines while taking buprenorphine and naloxone sublingual tablets, and warn patients to use benzodiazepines concurrently with buprenorphine and naloxone sublingual tablets only as directed by their healthcare provider.
Non-Benzodiazepine Central Nervous System (CNS) Depressants
Clinical Impact:
Due to additive pharmacologic effects, the concomitant use of non-benzodiazepine CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:
Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.2, 5.3)].
Examples:
Alcohol, non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and other opioids.
Inhibitors of CYP3A4
Clinical Impact:
The concomitant use of buprenorphine and CYP3A4 inhibitors can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of buprenorphine and naloxone sublingual tablets is achieved.
 
After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the buprenorphine plasma concentration will decrease [see Clinical Pharmacology (12.3)], potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to buprenorphine.
Intervention:
If concomitant use is necessary, consider dosage reduction of buprenorphine and naloxone sublingual tablets until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals.
 
If a CYP3A4 inhibitor is discontinued, consider increasing the buprenorphine and naloxone sublingual tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
Examples:
Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)
CYP3A4 Inducers
Clinical Impact:
The concomitant use of buprenorphine and CYP3A4 inducers can decrease the plasma concentration of buprenorphine [see Clinical Pharmacology (12.3)], potentially resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine.
 
After stopping a CYP3A4 inducer, as the effects of the inducer decline, the buprenorphine plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both therapeutic effects and adverse reactions and may cause serious respiratory depression.
Intervention:
If concomitant use is necessary, consider increasing the buprenorphine and naloxone sublingual tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
 
If a CYP3A4 inducer is discontinued, consider buprenorphine and naloxone sublingual tablets dosage reduction and monitor for signs of respiratory depression.
Examples:
Rifampin, carbamazepine, phenytoin
Antiretrovirals: Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Clinical Impact:
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are metabolized principally by CYP3A4. Efavirenz, nevirapine, and etravirine are known CYP3A inducers, whereas delaviridine is a CYP3A inhibitor. Significant pharmacokinetic interactions between NNRTIs (e.g., efavirenz and delavirdine) and buprenorphine have been shown in clinical studies, but these pharmacokinetic interactions did not result in any significant pharmacodynamic effects.
Intervention:
Patients who are on chronic buprenorphine and naloxone sublingual tablets treatment should have their dose monitored if NNRTIs are added to their treatment regimen.
Examples:
efavirenz, nevirapine, etravirine, delavirdine
Antiretrovirals: Protease inhibitors (PIs)
Clinical Impact:
Studies have shown some antiretroviral protease inhibitors (PIs) with CYP3A4 inhibitory activity (nelfinavir, lopinavir/ritonavir, ritonavir) have little effect on buprenorphine pharmacokinetic and no significant pharmacodynamic effects. Other PIs with CYP3A4 inhibitory activity (atazanavir and atazanavir/ritonavir) resulted in elevated levels of buprenorphine and norbuprenorphine, and patients in one study reported increased sedation. Symptoms of opioid excess have been found in postmarketing reports of patients receiving buprenorphine and atazanavir with and without ritonavir concomitantly.
Intervention:
Monitor patients taking buprenorphine and naloxone sublingual tablets and atazanavir with and without ritonavir, and reduce dose of buprenorphine and naloxone sublingual tablets if warranted.
Examples:
atazanavir, ritonavir
Antiretrovirals: Nucleoside reverse transcriptase inhibitors (NRTIs)
Clinical Impact:
Nucleoside reverse transcriptase inhibitors (NRTIs) do not appear to induce or inhibit the P450 enzyme pathway, thus no interactions with buprenorphine are expected.
Intervention:
None
Serotonergic Drugs
Clinical Impact:
The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention:
If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue buprenorphine and naloxone sublingual tablets if serotonin syndrome is suspected.
Examples:
Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:
MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma).
Intervention:
The use of buprenorphine and naloxone sublingual tablets is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples:
phenelzine, tranylcypromine, linezolid
Muscle Relaxants
Clinical Impact:
Buprenorphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:
Monitor patients receiving muscle relaxants and buprenorphine and naloxone sublingual tablets for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of buprenorphine and naloxone sublingual tablets and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact:
Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:
Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:
The concomitant use of anticholinergic drugs may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:
Monitor patients for signs of urinary retention or reduced gastric motility when buprenorphine and naloxone sublingual tablets are used concomitantly with anticholinergic drugs.


Table name:
aDrugs That May Decrease Tacrolimus Blood Concentrations
  a) This table is not all inclusive.
 Anticonvulsants  Antimicrobials
 carbamazepine  rifabutin
 phenobarbital  caspofungin
 phenytoin  rifampin
 Herbal Preparations  Other Drugs
 St. John’s Wort  sirolimus


Table name:
Interacting Drug Interaction
Antacids, sucralfate, multivitamins, and other products containing multivalent cations Moxifloxacin absorption is decreased. Administer AVELOX Tablet at least 4 hours before or 8 hours after these products. (2.2, 7.1, 12.3, 17.2)
Warfarin Anticoagulant effect of warfarin may be enhanced. Monitor prothrombin time/INR, watch for bleeding. (6.4, 7.2, 12.3)
Class IA and Class III antiarrhythmics: Proarrhythmic effect may be enhanced. Avoid concomitant use. (5.3, 7.4)


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine Decreased lamotrigine levels approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? CBZ epoxide May increase CBZ epoxide levels
Phenobarbital/Primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT) ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine Increased lamotrigine concentrations slightly more than 2-fold.
? valproate Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
blood dyscrasias -
seeCONTRAINDICATIONS
cancer
collagen vascular disease
congestive heart failure
diarrhea
elevated temperature
hepatic disorders
infectious hepatitis
jaundice
hyperthyroidism
poor nutritional state
steatorrhea
vitamin K deficiency


Table name:
blood dyscrasias - see cancer collagen vascular disease congestive heart failure
CONTRAINDICATIONS


diarrhea elevated temperature hepatic disorders infectious hepatitis jaundice



hyperthyroidism poor nutritional state steatorrhea vitamin K deficiency




Table name:
Interacting Drug Interaction
Multivalent cation-containing products including: antacids, sucralfate, multivitamins Decreased AVELOX absorption. Take AVELOX Tablet at least 4 hours before or 8 hours after these products. ( 2.2 , 7.1 , 12.3 )
Warfarin Anticoagulant effect enhanced. Monitor prothrombin time/INR, and bleeding. ( 6 , 7.2 , 12.3 )
Class IA and Class III antiarrhythmics: Proarrhythmic effect may be enhanced. Avoid concomitant use. ( 5.6 , 7.5 )
Antidiabetic agents Carefully monitor blood glucose. ( 5.11 , 7.3 )


Table name:
Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s) Recommendation Comments
Tizanidine Contraindicated Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)].
Theophylline Avoid Use (Plasma Exposure Likely to be Increased and Prolonged) Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions (5.6).]
Drugs Known to Prolong QT Interval Avoid Use Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.10) and Use in Specific Populations (8.5)].
Oral antidiabetic drugs Use with caution Glucose-lowering effect potentiated Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported . Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs. [see Adverse Reactions (6.1).]
Phenytoin Use with caution Altered serum levels of phenytoin (increased and decreased) To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after coadministration of ciprofloxacin with phenytoin.
Cyclosporine Use with caution (transient elevations in serum creatinine) Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs Use with caution (Increase in anticoagulant effect) The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole Use with caution Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after coadministration with ciprofloxacin [see Warnings and Precautions (5.15)].
Clozapine Use with caution Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs Use with caution Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil Use with caution 2-fold increase in exposure Monitor for sildenafil toxicity (see Pharmacokinetics -(12.3)-] .
Duloxetine Avoid Use 5-fold increase in duloxetine exposure If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx ® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products) Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2)]. Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels) Potentiation of ciprofloxacin toxicity may occur.


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class:
Drug Name
Effect on Concentration of Lopinavir or Concomitant Drug Clinical Comments
HIV-1 Antiviral Agents
HIV-1 Protease Inhibitor:
fosamprenavir/ritonavir
↓ amprenavir
↓ lopinavir
An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor:
indinavir*
↑ indinavir Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily [see Clinical Pharmacology ( 12.3)] . KALETRA once daily has not been studied in combination with indinavir.
HIV-1 Protease Inhibitor:
nelfinavir*
↑ nelfinavir
↑ M8 metabolite of nelfinavir
↓ lopinavir
KALETRA should not be administered once daily in combination with nelfinavir
[see Dosage and Administration ( 2) and Clinical Pharmacology ( 12.3)] .
HIV-1 Protease Inhibitor:
ritonavir*
↑ lopinavir Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor:
saquinavir*
↑ saquinavir The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily.
KALETRA once daily has not been studied in combination with saquinavir.
HIV-1 Protease Inhibitor:
tipranavir
↓ lopinavir AUC and C min KALETRA should not be administered with tipranavir (500 mg twice daily) co-administered with ritonavir (200 mg twice daily).
HIV CCR5 – Antagonist:
maraviroc
↑ maraviroc Concurrent administration of maraviroc with KALETRA will increase plasma levels of maraviroc. When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for Selzentry ® (maraviroc).
Non-nucleoside Reverse Transcriptase Inhibitor:
etravirine
↓ etravirine Because the reduction in the mean systemic exposures of etravirine in the presence of lopinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, no dose adjustment is required.
Non-nucleoside Reverse Transcriptase Inhibitors:
efavirenz*,
nevirapine*
↓ lopinavir KALETRA dose increase is recommended in all patients [see Dosage and Administration ( 2) and Clinical Pharmacology ( 12.3)] .
Increasing the dose of KALETRA tablets to 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) twice daily co-administered with efavirenz resulted in similar lopinavir concentrations compared to KALETRA tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz.
Increasing the dose of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice daily co-administered with efavirenz resulted in significantly higher lopinavir plasma concentrations compared to KALETRA tablets 400/100 mg twice daily without efavirenz.
KALETRA should not be administered once daily in combination with efavirenz or nevirapine
[see Dosage and Administration ( 2) and Clinical Pharmacology ( 12.3)] .
Non-nucleoside Reverse Transcriptase Inhibitor:
delavirdine
↑ lopinavir Appropriate doses of the combination with respect to safety and efficacy have not been established.
Non-nucleoside Reverse Transcriptase Inhibitor:
rilpivirine
↑ rilpivirine No dose adjustment is required.
Nucleoside Reverse Transcriptase Inhibitor:
didanosine
  KALETRA tablets can be administered simultaneously with didanosine without food.
For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food).
Nucleoside Reverse Transcriptase Inhibitor:
tenofovir
↑ tenofovir KALETRA increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir.
Nucleoside Reverse Transcriptase Inhibitors:
abacavir
zidovudine
↓ abacavir
↓ zidovudine
KALETRA induces glucuronidation; therefore, KALETRA has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown.
Other Agents
Antiarrhythmics e.g.:
amiodarone,
bepridil,
lidocaine (systemic),
quinidine
↑ antiarrhythmics Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA.
Anticancer Agents:
vincristine,
vinblastine,
dasatinib,
nilotinib
↑ anticancer agents Concentrations of these drugs may be increased when co-administered with KALETRA resulting in the potential for increased adverse events usually associated with these anticancer agents.
For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when KALETRA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor.
A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as KALETRA. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions.
Anticoagulants:
warfarin,
rivaroxaban
↑ rivaroxaban Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Avoid concomitant use of rivaroxaban and KALETRA. Co-administration of KALETRA and rivaroxaban is expected to result in increased exposure of rivaroxaban which may lead to risk of increased bleeding.
Anticonvulsants:
carbamazepine,
phenobarbital,
phenytoin
↓ lopinavir
↓ phenytoin
KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution.
KALETRA should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin.
In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA.
Anticonvulsants:
lamotrigine,
valproate
↓ lamotrigine
↓ or ↔ valproate
Co-administration of KALETRA and lamotrigine or valproate may decrease the exposure of lamotrigine or valproate. A dose increase of lamotrigine or valproate may be needed when co-administered with KALETRA and therapeutic concentration monitoring for lamotrigine may be indicated; particularly during dosage adjustments.
Antidepressant:
bupropion
↓ bupropion
↓ active metabolite,
hydroxybupropion
Concurrent administration of bupropion with KALETRA may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion.
Antidepressant:
trazodone
↑ trazodone Concomitant use of trazodone and KALETRA may increase concentrations of trazodone. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered.
Anti-infective:
clarithromycin
↑ clarithromycin For patients with renal impairment, the following dosage adjustments should be considered: For patients with CL CR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients with CL CR < 30 mL/min the dose of clarithromycin should be decreased by 75%. No dose adjustment for patients with normal renal function is necessary.
Antifungals:
ketoconazole*,
itraconazole,
voriconazole
↑ ketoconazole
↑ itraconazole
↓ voriconazole
High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended.
Co-administration of voriconazole with KALETRA has not been studied. However, a study has been shown that administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%; therefore, co-administration of KALETRA and voriconazole may result in decreased voriconazole concentrations and the potential for decreased voriconazole effectiveness and should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Otherwise, alternative antifungal therapies should be considered in these patients.
Anti-gout:
colchicine
↑ colchicine Patients with renal or hepatic impairment should not be given colchicine with KALETRA.
Treatment of gout flares-co-administration of colchicine in patients on KALETRA:
0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days.
Prophylaxis of gout flares-co-administration of colchicine in patients on KALETRA:
If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.
If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.
Treatment of familial Mediterranean fever (FMF)-co-administration of colchicine in patients on KALETRA:
Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Antimycobacterial:
bedaquiline
↑ bedaquiline Bedaquiline should only be used with KALETRA if the benefit of co-administration outweighs the risk [see Pharmacokinetics ( 12.3)] .
Antimycobacterial:
rifabutin*
↑ rifabutin and rifabutin metabolite Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary.
Antimycobacterial:
rifampin
↓ lopinavir May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents. A study evaluated combination of rifampin 600 mg once daily, with KALETRA 800/200 mg twice daily or KALETRA 400/100 mg + ritonavir 300 mg twice daily. Pharmacokinetic and safety results from this study do not allow for a dose recommendation. Nine subjects (28%) experienced a ≥ grade 2 increase in ALT/AST, of which seven (21%) prematurely discontinued study per protocol. Based on the study design, it is not possible to determine whether the frequency or magnitude of the ALT/AST elevations observed is higher than what would be seen with rifampin alone [see Clinical Pharmacology ( 12.3) for magnitude of interaction ].
Antiparasitic:
atovaquone
↓ atovaquone Clinical significance is unknown; however, increase in atovaquone doses may be needed.
Antipsychotics: quetiapine ↑ quetiapine Initiation of KALETRA in patients taking quetiapine:
Consider alternative antiretroviral therapy to avoid increases in quetiapine exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring.

Initiation of quetiapine in patients taking KALETRA:
Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.
Benzodiazepines: parenterally administered midazolam ↑ midazolam Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, KALETRA should not be given with orally administered midazolam [see Contraindications ( 4)] . If KALETRA is co-administered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.
Contraceptive:
ethinyl estradiol*
↓ ethinyl estradiol Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended.
Corticosteroids (systemic): e.g.
budesonide,
dexamethasone,
prednisone
↓ lopinavir
↑ glucocorticoids
Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly.
Concomitant use may result in increased steroid concentrations and reduced serum cortisol concentrations. Concomitant use of glucocorticoids that are metabolized by CYP3A, particularly for long-term use, should consider the potential benefit of treatment versus the risk of systemic corticosteroid effects. Concomitant use may increase the risk for development of systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression.
Dihydropyridine Calcium Channel Blockers: e.g.
felodipine,
nifedipine,
nicardipine
↑ dihydropyridine calcium channel blockers Caution is warranted and clinical monitoring of patients is recommended.
Disulfiram/metronidazole   KALETRA oral solution contains alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).
Endothelin Receptor Antagonists:
bosentan
↑ bosentan Co-administration of bosentan in patients on KALETRA:
In patients who have been receiving KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Co-administration of KALETRA in patients on bosentan:
Discontinue use of bosentan at least 36 hours prior to initiation of KALETRA.
After at least 10 days following the initiation of KALETRA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
HCV-Protease Inhibitor:
boceprevir
↓ lopinavir
↓ boceprevir
↓ ritonavir
It is not recommended to co-administer KALETRA and boceprevir. Concomitant administration of KALETRA and boceprevir reduced boceprevir, lopinavir and ritonavir steady-state exposures [see Clinical Pharmacology ( 12.3)] .
HCV-Protease Inhibitor:
simeprevir
↑ simeprevir It is not recommended to co-administer KALETRA and simeprevir.
HMG-CoA Reductase Inhibitors:
atorvastatin
rosuvastatin
↑ atorvastatin
↑ rosuvastatin
Use atorvastatin with caution and at the lowest necessary dose. Titrate rosuvastatin dose carefully and use the lowest necessary dose; do not exceed rosuvastatin 10 mg/day. See Drugs with No Observed or Predicted Interactions with KALETRA ( 7.4) and Clinical Pharmacology ( 12.3) for drug interaction data with other HMG-CoA reductase inhibitors.
Immunosuppressants: e.g.
cyclosporine,
tacrolimus,
sirolimus
↑ immunosuppressants Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA.
Inhaled or Intranasal Steroids e.g.:
fluticasone,
budesonide
↑ glucocorticoids Concomitant use of KALETRA and fluticasone or other glucocorticoids that are metabolized by CYP3A is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects. Concomitant use may result in increased steroid concentrations and reduce serum cortisol concentrations.
Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during postmarketing use in patients when certain ritonavir-containing products have been co-administered with fluticasone propionate or budesonide.
Long-acting beta-adrenoceptor Agonist:
salmeterol
↑ salmeterol Concurrent administration of salmeterol and KALETRA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Narcotic Analgesics:
methadone,*
fentanyl
↓ methadone
↑ fentanyl
Dosage of methadone may need to be increased when co-administered with KALETRA.
Concentrations of fentanyl are expected to increase. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with KALETRA.
PDE5 inhibitors:
avanafil,
sildenafil,
tadalafil,
vardenafil
↑ avanafil
↑ sildenafil
↑ tadalafil
↑ vardenafil
Do not use KALETRA with avanafil because a safe and effective avanafil dosage regimen has not been established.
Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs is expected to substantially increase their concentrations and may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection.
Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH):
Sildenafil (Revatio ®) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with KALETRA [see Contraindications ( 4)] .
The following dose adjustments are recommended for use of tadalafil (Adcirca ®) with KALETRA:
Co-administration of ADCIRCA in patients on KALETRA:
In patients receiving KALETRA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.
Co-administration of KALETRA in patients on ADCIRCA:
Avoid use of ADCIRCA during the initiation of KALETRA. Stop ADCIRCA at least 24 hours prior to starting KALETRA. After at least one week following the initiation of KALETRA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.
Use of PDE5 inhibitors for erectile dysfunction:
It is recommended not to exceed the following doses:
  • Sildenafil: 25 mg every 48 hours
  • Tadalafil: 10 mg every 72 hours
  • Vardenafil: 2.5 mg every 72 hours
Use with increased monitoring for adverse events.
*    see Clinical Pharmacology ( 12.3) for magnitude of interaction.


Table name:
Factors   Dosage Adjustment of aripiprazole
 Known CYP2D6 Poor Metabolizers  Administer half of usual dose
 Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors  Administer a quarter of usual dose
 Strong CYP2D6 or CYP3A4 inhibitors  Administer half of usual dose
 Strong CYP2D6 and CYP3A4 inhibitors  Administer a quarter of usual dose
 Strong CYP3A4 inducers  Double usual dose over 1 to 2 weeks


Table name:
AED Co-administered
AED Concentration
Topiramate Concentration
Phenytoin
NCor25%increasea
48%decrease
Carbamazepine(CBZ)
NC
40%decrease
CBZepoxideb
NC 
            NE
Valproic acid
11%decrease
14%decrease
Phenobarbital
NC
            NE
Primidone
NC
           NE
Lamotrigine
NCatTPM dosesupto400  mg/day 
         13%decrease


Table name:
DRUG DESCRIPTION OF INTERACTION
Corticosteroids Decreases plasma salicylate level; tapering doses of steroids may promote salicylism.
Acidifying Agents Increases plasma salicylate level.
Alkalizing Agents Decreased plasma salicylate levels.


Table name:
Table 4. Established and Other Potentially Significant Drug Interactions
↓ = Decreased (induces lamotrigine glucuronidation).
↑ = Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
Concomitant Drug 
Effect on Concentration
of Lamotrigine or
Concomitant Drug
Clinical Comment 
Estrogen-containing oral 
contraceptive preparations
containing 30 mcg 
ethinylestradiol and 150 mcg
levonorgestrel 
↓ lamotrigine 


↓ levonorgestrel 
Decreased lamotrigine levels 
approximately 50%. 

Decrease in levonorgestrel 
component by 19%. 
Carbamazepine and
carbamazepine epoxide 
↓ lamotrigine 


? carbamazepine
  epoxide 
Addition of carbamazepine 
decreases lamotrigine 
concentration approximately 40%. 
May increase carbamazepine
epoxide levels. 
Phenobarbital/Primidone 
↓ lamotrigine 
Decreased lamotrigine 
concentration approximately 40%. 
Phenytoin 
↓ lamotrigine 
Decreased lamotrigine 
concentration approximately 40%. 
Rifampin 
↓ lamotrigine
Decreased lamotrigine 
AUC approximately 40%. 
Valproate 
↑ lamotrigine 


? valproate 
Increased lamotrigine 
concentrations slightly more than 
2-fold. 
Decreased valproate concentrations 
an average of 25% over a 3-week 
period then stabilized in healthy 
volunteers; no change in controlled 
clinical trials in epilepsy patients. 


Table name:
Interacting Drug Interaction
Theophylline Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin Monitor phenytoin level (7)
Methotrexate Monitor for methotrexate toxicity (7)
Cyclosporine May increase serum creatinine. Monitor serum creatinine (7)
Multivalent cation-containing products including antacids, metal cations or didanosine Decreased ciprofloxacin tablets absorption. Take 2 hours before or 6 hours after ciprofloxacin tablets (7)


Table name:
DRUG DESCRIPTION OF INTERACTION
Corticosteroids Decreases plasma salicylate level; tapering doses of steroids may promote salicylism.
Acidifying Agents Increases plasma salicylate level.
Alkalinizing Agents Decreased plasma salicylate levels.


Table name:
Table 4. Other Potentially Significant Drug Interactions
Concomitant Drug Class or Food Noted or Anticipated Outcome Clinical Comment
HMG-Co A Reductase Inhibitors:
atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin
Pharmacokinetic and/or pharmacodynamic interaction: the addition of one drug to a stable long-term regimen of the other has resulted in myopathy and rhabdomyolysis (including a fatality) P-gp substrate; rhabdomyolysis has been reported Weigh the potential benefits and risks and carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during initial therapy; monitoring CPK (creatine phosphokinase) will not necessarily prevent the occurrence of severe myopathy.
Other Lipid-Lowering Drugs:
fibrates, gemfibrozil
Digitalis Glycosides:
digoxin


Table name:
Antibiotics Antineoplastic Antifungals Anti-Inflammatory Drugs Gastrointestinal Agents Immunosuppressives Other Drugs
ciprofloxacin melphalan amphotericin B azapropazon cimetidine tacrolimus fibric acid derivatives
(e.g., bezafibrate, fenofibrate)
gentamicin ketoconazole colchicine ranitidine methotrexate
tobramycin diclofenac
trimethoprim 
with sulfamethoxazole
naproxen
vancomycin sulindac


Table name:
Table 3Drugs that Can Increase the Risk of Bleeding
Drug  Class
Specific  Drugs
Anticoagulants 
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin 
Antiplatelet Agents 
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine 
Nonsteroidal Anti-Inflammatory Agents 
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac 
Serotonin Reuptake Inhibitors 
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone 


Table name:
I. Due to the competition of salicylate with other drugs for binding to serum albumin the following drug interactions may occur:
DRUG DESCRIPTION OF INTERACTION
Sulfonylureas Hypoglycemia potentiated.
Methotrexate Decreases tubular reabsorption; clinical toxicity from methotrexate can result.
Oral Anticoagulants Increased bleeding.
II. Drugs changing salicylate levels by altering renal tubular reabsorption:
DRUG DESCRIPTION OF INTERACTION
Corticosteroids Decreases plasma salicylate level; tapering doses of steroids may promote salicylism.
Acidifying Agents Increases plasma salicylate levels.
Alkanizing Agents Decreased plasma salicylate levels.
III. Drugs with complicated interactions with salicylates:
DRUG DESCRIPTION OF INTERACTION
Heparin Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients.
Pyrazinamide Inhibits pyrazinamide-induced hyperuricemia.
Uricosuric Agents Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited.
The following alterations of laboratory tests have been reported during salicylate therapy:
LABORATORY TESTS EFFECT OF SALICYLATES
Thyroid Function Decreased PBI; increased t3 uptake.
Urinary Sugar False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5g q.d.).
5-Hydroxyindole acetic acid False negative with fluorometric test.
Acetone ketone bodies False positive FeCI3 in Gerhardt reaction; red color persists with boiling.
17-OH corticosteroids False reduced values with >4.8g q.d. salicylate.
Vanilmandelic acid False reduced values.
Uric Acid May increase or decrease depending on dose.
Prothrombin Decreased levels; slightly increased prothrombin time.


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide

Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide






Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T and T levels and increase TSH, although all values remain within normal limits in most patients. 4 3
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate










Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
  Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration   Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen





Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid


Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)





Administration of these agents with levothyroxine results in an initial transient increase in FT . Continued administration results in a decrease in serum T and normal FT and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T and T to TBG and transthyretin. An initial increase in serum FT , is followed by return of FT to normal levels with sustained therapeutic serum salicylate concentrations, although total-T levels may decrease by as much as 30%. 4 4 4 4 3 4 4 4
  Drugs that may alter T 4 and T 3 metabolism
  Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin


Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. 4
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)




Administration of these enzyme inhibitors decrease the peripheral conversion of T to T , leading to decreased T levels. However, serum T levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T and T levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T concentrations by 30% with minimal change in serum T levels. However, long-term glucocorticoid therapy may result in slightly decreased T and T levels due to decreased TBG production (see above). 4 3 3 4 3 4 3 4 3 4
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives

Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)


Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin




Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2

Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin

Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of I, I, and Tc. 123 131 99m
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics









These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 3Drugs that Can Increase the Risk of Bleeding
Drug  Class
Specific  Drugs
Anticoagulants 
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin 
Antiplatelet Agents 
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine 
Nonsteroidal Anti-Inflammatory Agents 
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac 
Serotonin Reuptake Inhibitors 
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone 


Table name:
Table 5: Effects on Steady-State Fexofenadine Pharmacokinetics After 7 Days of Coadministration With Fexofenadine Hydrochloride 120 mg Every 12 Hours in Healthy Adult Subjects (n = 24)
 Concomitant Drug  CmaxSS (Peak plasma concentration)  AUCss(0-12h) (Extent of systemic exposure)
  Erythromycin (500 mg every 8 hrs)   +82%   +109%
  Ketoconazole (400 mg once daily)   +135%   +164%


Table name:
AED Coadministered AED Concentration Topiramate Concentration
Phenytoin NC or 25% increasea 48% decrease
Carbamazepine (CBZ) NC 40% decrease
CBZ epoxideb NC NE
Valproic acid 11% decrease 14% decrease
Phenobarbital NC NE
Primidone NC NE
Lamotrigine NC at TPM doses up to 400 mg/day 13% decrease


Table name:
blood dyscrasias -
seeCONTRAINDICATIONS
cancer
collagen vascular disease
congestive heart failure
diarrhea
elevated temperature
hepatic disorders
infectious hepatitis
jaundice
hyperthyroidism
poor nutritional state
steatorrhea
vitamin K deficiency


Table name:
Table 3: Established and Other Potentially Significant Drug Interactions: Alteration in CERDELGA Dosage May Be Recommended Based on Drug Interaction Studies or on Predicted Interaction in EMs and IMs
Recommended CERDELGA Dosage, by CYP2D6 Metabolizer Status
CYP450 Inhibitors EM IM
Strong or Moderate CYP2D6 inhibitors concomitantly with Strong or Moderate CYP3A inhibitors Contraindicated Contraindicated
Strong CYP2D6 inhibitors
e.g., paroxetine
84 mg once daily 84 mg once daily
Moderate CYP2D6 inhibitors
e.g., terbinafine
84 mg once daily 84 mg once daily
Strong CYP3A inhibitors
e.g., ketoconazole
84 mg once daily Contraindicated
Moderate CYP3A inhibitors
e.g., fluconazole
84 mg once daily Not recommended


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine Decreased lamotrigine levels approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? CBZ epoxide May increase CBZ epoxide levels.
Phenobarbital/Primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT) ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine Increased lamotrigine concentrations slightly more than 2 fold.
? valproate Decreased valproate concentrations an average of 25% over a 3 week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
CYP2C19 or CYP3A4 Inducers
Clinical Impact: Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology ( 12.3)] .
Intervention: St. John’s Wort, rifampin: Avoid concomitant use with omeprazole [see Warnings and Precautions ( 5.9)] .

Ritonavir-containing products: see prescribing information for specific drugs.
CYP2C19 or CYP3A4 Inhibitors
Clinical Impact: Increased exposure of omeprazole [see Clinical Pharmacology ( 12.3)] .
  Intervention: Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered.

See prescribing information for voriconazole.


Table name:
Antiarrhythmics Dofetilide Concomitant administration with digoxin was associated with a higher rate of torsades de pointes.
Moricizine Reported to increase PR interval and QRS duration. There are reports of first degree atrioventricular block or bundle branch block developing with digitalis administration. The known effects of moricizine on calcium conductance may explain the effects on atrioventricular node conduction.
Sotalol Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
Parathyroid Hormone Analog Teriparatide Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid Supplement Thyroid Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics Epinepherine Can increase the risk of cardiac arrhythmias.
Norepinephrine
Dopamine
Neuromuscular Blocking Agents Succinylcholine May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.
Supplements Calcium If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers Additive effects on AV node conduction can result in complete heart block.


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function.
Drugs that may alter T4 and T3 serum transport - but FT4 concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin/Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens/Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non-Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4 . Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ³ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias
and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123 I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Drugs That Interfere with Hemostasis
Clinical Impact: • Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of naproxen or naproxen sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: Concomitant use of naproxen or naproxen sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen or naproxen sodium is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE-inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: • During concomitant use of naproxen or naproxen sodium and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of naproxen or naproxen sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen or naproxen sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact: The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of naproxen or naproxen sodium and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen or naproxen sodium and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of naproxen or naproxen sodium and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of naproxen or naproxen sodium and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of naproxen or naproxen sodium and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of naproxen or naproxen sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of naproxen or naproxen sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact: Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention: Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen or naproxen sodium is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed release tablets are not recommended.
Cholestyramine
Clinical Impact: Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention: Concomitant administration of cholestyramine with naproxen or naproxen sodium is not recommended.
Probenecid
Clinical Impact: Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention: Patients simultaneously receiving naproxen or naproxen sodium and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact: Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention: Patients simultaneously receiving naproxen or naproxen sodium and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.


Table name:
Calcium Channel Blockers Antifungals Antibiotics Glucocorticoids Other Drugs                   
diltiazem fluconazole azithromycin methylprednisolone     allopurinol                           
nicardipine itraconazole clarithromycin amiodarone
verapamil ketoconazole erythromycin bromocriptine
quinupristin/ colchicine
voriconazole dalfopristin danazol
imatinib
metoclopramide
nefazodone
oral contraceptives


Table name:
Drugs That Interfere with Hemostasis
Clinical Impact: • Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. S er otonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of VOLTAREN® GEL with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].
Intervention: Concomitant use of VOLTAREN® GEL and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions     (5.11)]. VOLTAREN® GEL is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or betablockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: • During concomitant use of VOLTAREN® GEL and ACE-inhibitors, ARBs, or beta- blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of VOLTAREN® GEL and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. •When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of VOLTAREN® GEL with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ see Warnings and Precautions (5.6)].
Digoxin
Clinical Impact: The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of VOLTAREN® GEL and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of VOLTAREN® GEL and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of VOLTAREN® GEL and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of VOLTAREN® GEL and cyclosporine may increase cyclosporine's nephrotoxicity.
Intervention: During concomitant use of VOLTAREN® GEL and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention: The concomitant use of diclofenac with other NSAIDs or salicylates is notrecommended.
Pemetrexed
Clinical Impact: Concomitant use of VOLTAREN® GEL and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of VOLTAREN® GEL and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and Gl toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.


Table name:
Drug interaction Associated with increased Risk of Myopathy/Rhabdomyolysis (2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3) 
*For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Interacting Agents
Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol
Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone
Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine
Do not exceed 20 mg simvastatin daily
Lomitapide
For patients with HoFH, do not exceed 20 mg simvastatin daily*
Grapefruit juice
Avoid grapefruit juice


Table name:
Inhibitors of CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6
Clinical Impact: Methadone undergoes hepatic N-demethylation by several cytochrome P450 (CYP) isoforms, including CYP3A4, CYP2B6, CYP2C19, CYP2C9, and CYP2D6. The concomitant use of methadone hydrochloride tablets and CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitors can increase the plasma concentration of methadone, resulting in increased or prolonged opioid effects, and may result in a fatal overdose, particularly when an inhibitor is added after a stable dose of methadone hydrochloride tablets is achieved. These effects may be more pronounced with concomitant use of drugs that inhibit more than one of the CYP enzymes listed above. After stopping a CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitor, as the effects of the inhibitor decline, the methadone plasma concentration can decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy or withdrawal symptoms in patients physically dependent on methadone.
Intervention: If concomitant use is necessary, consider dosage reduction of methadone hydrochloride tablets until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitor is discontinued, follow patients for signs of opioid withdrawal and consider increasing the methadone hydrochloride tablets dosage until stable drug effects are achieved.
Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir), fluconazole, fluvoxamine, some selective serotonin reuptake inhibitors (SSRIs) (e.g., sertraline, fluvoxamine)
Inducers of CYP3A4, CYP2B6, CYP2C19, or CYP2C9
Clinical Impact: The concomitant use of methadone hydrochloride tablets and CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers can decrease the plasma concentration of methadone [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of withdrawal symptoms in patients physically dependent on methadone. These effects could be more pronounced with concomitant use of drugs that can induce multiple CYP enzymes. After stopping a CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducer, as the effects of the inducer decline, the methadone plasma concentration can increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression, sedation, or death.
Intervention: If concomitant use is necessary, consider increasing the methadone hydrochloride tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducer is discontinued, consider methadone hydrochloride tablets dosage reduction and monitor for signs of respiratory depression and sedation.
Examples: Rifampin, carbamazepine, phenytoin, St. John’s Wort, Phenobarbital
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death.
Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.6)].
Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Potentially Arrhythmogenic Agents
Clinical Impact: Pharmacodynamic interactions may occur with concomitant use of methadone and potentially arrhythmogenic agents or drugs capable of inducing electrolyte disturbances (hypomagnesemia, hypokalemia).
Intervention: Monitor patients closely for cardiac conduction changes.
Examples: Drugs known to have potential to prolong QT interval: Class I and III antiarrhythmics, some neuroleptics and tricyclic antidepressants, and calcium channel blockers. Drugs capable of inducing electrolyte disturbances: Diuretics, laxatives, and, in rare cases, mineralocortocoid hormones.
Serotonergic Drugs
Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Warnings and Precautions (5.8)].
Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue methadone hydrochloride tablets if serotonin syndrome is suspected.
Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome [see Warnings and Precautions (5.8)] or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)].
Intervention: The use of methadone hydrochloride tablets is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact: May reduce the analgesic effect of methadone hydrochloride tablets and/or precipitate withdrawal symptoms.
Intervention: Avoid concomitant use.
Examples: butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact: Methadone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of methadone hydrochloride tablets and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when methadone hydrochloride tablets are used concomitantly with anticholinergic drugs.


Table name:
Table 15: Clinically Important Drug Interactions with Aripiprazole Tablets:
Concomitant Drug
Name or Drug Class
Clinical Rationale Clinical Recommendation
Strong CYP3A4 Inhibitors
(e.g., itraconazole,
clarithromycin) or strong
CYP2D6 inhibitors
(e.g., quinidine, fluoxetine,
paroxetine)
The concomitant use of aripiprazole
tablets with strong CYP3A4 or CYP2D6
inhibitors increased the exposure of
aripiprazole tablets compared to the use
of aripiprazole tablets alone [see CLINICAL
PHARMACOLOGY (12.3)].
With concomitant use of
aripiprazole tablets with a
strong CYP3A4 inhibitor or
CYP2D6 inhibitor, reduce
the aripiprazole tablets
dosage[see DOSAGE AND
ADMINISTRATION (2.7)].
Strong CYP3A4 Inducers
(e.g., carbamazepine,
rifampin)
The concomitant use of aripiprazole
tablets and carbamazepine decreased the
exposure of aripiprazole tablets compared
to the use of aripiprazole tablets alone
[see CLINICAL PHARMACOLOGY (12.3)].
With concomitant use of
aripiprazole tablets with
a strong CYP3A4 inducer,
consider increasing
the aripiprazole tablets
dosage [see DOSAGE AND
ADMINISTRATION (2.7)].
Antihypertensive Drugs Due to its alpha adrenergic antagonism,
aripiprazole tablets has the potential
to enhance the effect of certain
antihypertensive agents.
Monitor blood pressure and
adjust dose accordingly
[see WARNINGS AND
PRECAUTIONS (5.7)].
 
Benzodiazepines
(e.g., lorazepam)
The intensity of sedation was greater with
the combination of oral aripiprazole and
lorazepam as compared to that observed
with aripiprazole alone.The orthostatic
hypotension observed was greater with
the combination as compared to that
observed with lorazepam alone [see
WARNINGS AND PRECAUTIONS (5.7)]
Monitor sedation and blood
pressure. Adjust dose
accordingly.


Table name:
Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.Refer to PRECAUTIONS, Drug Interactions for information regarding table.
 albuterol,  famotidine  nizatidine
  systemic and inhaled  felodipine  norfloxacin
 amoxicillin  finasteride  ofloxacin
 ampicillin,  hydrocortisone  omeprazole
  with or without  isoflurane  prednisone, prednisolone
  sulbactam  isoniazid  ranitidine
 atenolol  isradipine  rifabutin
 azithromycin  influenza vaccine  roxithromycin
 caffeine,  ketoconazole  sorbitol
   dietary ingestion  lomefloxacin  (purgative doses do not
 cefaclor  mebendazole  inhibit theophylline
 co-trimoxazole  medroxyprogesterone  absorption)
 (trimethoprim and  methylprednisolone  sucralfate
  sulfamethoxazole)  metronidazole  terbutaline, systemic
 diltiazem  metoprolol  terfenadine
 dirithromycin  nadolol  tetracycline
 enflurane  nifedipine  tocainide


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
 Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)  Avoid atorvastatin
 HIV protease inhibitor (lopinavir plus ritonavir)  Use with caution and lowest dose necessary
 Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)  Do not exceed 20 mg atorvastatin daily
 HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
 Do not exceed 40 mg atorvastatin daily


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
↓ = Decreased (induces lamotrigine glucuronidation).
↑ = Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
Concomitant  Drug
Effect  on
  Concentration  of
  Lamotrigine  or
  Concomitant  Drug



Clinical  Comment
Estrogen-containing oral
 contraceptive preparations
 containing 30 mcg
 ethinylestradiol and 150 mcg 
levonorgestrel 
↓ lamotrigine

↓ levonorgestrel 

Decreased lamotrigine concentrations
approximately 50%.
Decrease in levonorgestrel component by 19%. 
Carbamazepine and
 carbamazepine epoxide 

↓ lamotrigine 

? carbamazepine
 epoxide 
Addition of carbamazepine decreases
lamotrigine concentration approximately 40%. 
May increase carbamazepine epoxide levels. 
Lopinavir/ritonavir 

↓ lamotrigine 

Decreased lamotrigine concentration
approximately 50%. 
Atazanavir/ritonavir
↓ lamotrigine
Decreased lamotrigine AUC
approximately 32%.
Phenobarbital/primidone
↓ lamotrigine
Decreased lamotrigine concentration
approximately 40%.
Phenytoin
↓ lamotrigine
Decreased lamotrigine concentration
approximately 40%.
Rifampin
↓ lamotrigine
Decreased lamotrigine AUC approximately
40%.

Valproate                             


↑ lamotrigine

? valproate

Increased lamotrigine concentrations slightly
more than 2-fold.
There are conflicting study results regarding
effect of lamotrigine on valproate
concentrations: 1) a mean 25% decrease in
valproate concentrations in healthy volunteers,
2) no change in valproate concentrations in
controlled clinical trials in patients with
epilepsy.


Table name:
Table 8: Effect of Voriconazole on Pharmacokinetics of Other Drugs [see Clinical Pharmacology (12.3)]
Drug/Drug Class
(Mechanism of Interaction by Voriconazole)
Drug Plasma Exposure
(Cmax and AUCτ)
Recommendations for Drug Dosage Adjustment/Comments
SirolimusResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects
(CYP3A4 Inhibition)
Significantly Increased Contraindicated
Rifabutin
(CYP3A4 Inhibition)
Significantly Increased Contraindicated
Efavirenz (400 mg q24h)Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects
(CYP3A4 Inhibition)
Significantly Increased Contraindicated
 
Efavirenz (300 mg q24h)
(CYP3A4 Inhibition)
Slight Increase in AUCτ When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)(CYP3A4 Inhibition) No Significant Effect of Voriconazole on Ritonavir Cmax or AUCτ Contraindicated because of significant reduction of voriconazole Cmax and AUCτ
 
Low-dose Ritonavir (100 mg q12h) Slight Decrease in Ritonavir Cmax and AUCτ Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole Cmax and AUCτ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine
(CYP3A4 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids
(CYP450 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Contraindicated
Cyclosporine
(CYP3A4 Inhibition)
AUCτ Significantly Increased; No Significant Effect on Cmax When initiating therapy with VFEND in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When VFEND is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
MethadoneResults based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for 4 days voriconazole to subjects receiving a methadone maintenance dose (30–100 mg q24h) (CYP3A4 Inhibition) Increased Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl (CYP3A4 Inhibition) Increased Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7)]
Alfentanil (CYP3A4 Inhibition) Significantly Increased Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with VFEND. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [see Drug Interactions (7)].
Oxycodone (CYP3A4 Inhibition) Significantly Increased Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7)].
NSAIDsNon-Steroidal Anti-Inflammatory Drug including. ibuprofen and diclofenac
(CYP2C9 Inhibition)
Increased Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed [see Drug Interactions (7)].
Tacrolimus
(CYP3A4 Inhibition)
Significantly Increased When initiating therapy with VFEND in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When VFEND is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin
(CYP2C9 Inhibition)
Significantly Increased Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition) Increased Monitoring for adverse events related to oral contraceptives is recommended during coadministration.
Warfarin
(CYP2C9 Inhibition)
Prothrombin Time Significantly Increased Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed.
Omeprazole
(CYP2C19/3A4 Inhibition)
Significantly Increased When initiating therapy with VFEND in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors
(CYP3A4 Inhibition)
In Vivo Studies Showed No Significant Effects on Indinavir Exposure No dosage adjustment for indinavir when coadministered with VFEND
 
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism
(Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors
(CYP3A4 Inhibition)
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs
(Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity related to NNRTI
Benzodiazepines
(CYP3A4 Inhibition)
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism
(Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.
HMG-CoA Reductase Inhibitors (Statins)
(CYP3A4 Inhibition)
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism
(Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers
(CYP3A4 Inhibition)
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism
(Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics
(CYP2C9 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids
(CYP3A4 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed.
Everolimus
(CYP3A4 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Concomitant administration of voriconazole and everolimus is not recommended.


Table name:
Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.*
* Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol,diltiazemmedroxyprogesteroneroxithromycin
   systemic and inhaleddirithromycinmethylprednisolonesorbitol
amoxicillinenfluranemetronidazole   (purgative doses
ampicillin,famotidinemetoprolol   do not inhibit
   with or withoutfelodipinenadolol   theophylline
   sulbactamfinasteridenifedipine   absorption)
atenololhydrocortisonenizatidinesucralfate
azithromycinisofluranenorfloxacinterbutaline, systemic
caffeine,isoniazidofloxacinterfenadine
   dietary ingestionisradipineomeprazoletetracycline
cefaclorinfluenza vaccineprednisone,tocainide
co-trimoxazoleketoconazole   prednisolone
   (trimethoprim andlomefloxacinranitidine
   sulfamethoxazole)mebendazolerifabutin


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide

Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide






Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T and T levels and increase TSH, although all values remain within normal limits in most patients. 4 3
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate










Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
  Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration   Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen





Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid


Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)





Administration of these agents with levothyroxine results in an initial transient increase in FT . Continued administration results in a decrease in serum T and normal FT and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T and T to TBG and transthyretin. An initial increase in serum FT , is followed by return of FT to normal levels with sustained therapeutic serum salicylate concentrations, although total-T levels may decrease by as much as 30%. 4 4 4 4 3 4 4 4
  Drugs that may alter T 4 and T 3 metabolism
  Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin


Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. 4
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)




Administration of these enzyme inhibitors decrease the peripheral conversion of T to T , leading to decreased T levels. However, serum T levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T and T levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T concentrations by 30% with minimal change in serum T levels. However, long-term glucocorticoid therapy may result in slightly decreased T and T levels due to decreased TBG production (see above). 4 3 3 4 3 4 3 4 3 4
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives

Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)


Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin




Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2

Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin

Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of I, I, and Tc. 123 131 99m
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics









These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 11 Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies (see CLINICAL PHARMACOLOGY, for Magnitude of Interaction, Tables 6 and 7)
Concomitant Drug Class: Drug Name Effect on Concentration Clinical Comment
HIV-Antiviral Agents
Non-nucleoside Reverse Transcriptase Inhibitors: Appropriate doses for these combinations, with respect to safety and efficacy, have not been established.
delavirdine ↑ nelfinavir
↓ delavirdine
nevirapine ↓ nelfinavir (Cmin)
Nucleoside Reverse Transcriptase Inhibitor:
didanosine
It is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after VIRACEPT (given with food).
Protease Inhibitors: Appropriate doses for these combinations, with respect to safety and efficacy, have not been established.
indinavir ↑ nelfinavir
↑ indinavir
ritonavir ↑ nelfinavir
saquinavir ↑ saquinavir
Other Agents
Anti-coagulant:
warfarin
warfarin Coadministration of warfarin and VIRACEPT may affect concentrations of warfarin. It is recommended that the INR (international normalized ratio) be monitored carefully during treatment with VIRACEPT, especially when commencing therapy.
Anti-convulsants: May decrease nelfinavir plasma concentrations. VIRACEPT may not be effective due to decreased nelfinavir plasma concentrations in patients taking these agents concomitantly.
carbamazepine
phenobarbital
↓ nelfinavir
Anti-convulsant: Phenytoin plasma/serum concentrations should be monitored; phenytoin dose may require adjustment to compensate for altered phenytoin concentration.
phenytoin ↓ phenytoin
Anti-depressant: trazodone ↑ trazodone Concomitant use of trazodone and VIRACEPT may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as VIRACEPT, the combination should be used with caution and a lower dose of trazodone should be considered.
Anti-gout
colchicine
↑ colchicine Treatment of gout flares–
coadministration of colchicine in patients on VIRACEPT:
0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days.
Prophylaxis of gout-flares–
coadministration of colchicine in patients on VIRACEPT:
If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.
If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.

Treatment of familial Mediterranean fever (FMF)–
coadministration of colchicine in patients on VIRACEPT:
Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Patients with renal or hepatic impairment should not be given colchicine with VIRACEPT.
Anti-Mycobacterial: It is recommended that the dose of rifabutin be reduced to one-half the usual dose when administered with VIRACEPT; 1250 mg BID is the preferred dose of VIRACEPT when coadministered with rifabutin.
rifabutin ↑ rifabutin
↓ nelfinavir
  (750 mg TID)
↔ nelfinavir
  (1250 mg BID)
Endothelin receptor antagonists:
bosentan
↑ bosentan Coadministration of bosentan in patients on VIRACEPT or coadministration of VIRACEPT in patients on bosentan: Start at or adjust bosentan to 62.5 mg once daily or every other day based upon individual tolerability.
HMG-CoA Reductase Inhibitor: Use lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin or fluvastatin in combination with VIRACEPT.
atorvastatin ↑ atorvastatin
rosuvastatin ↑ rosuvastatin
Immuno-suppressants: Plasma concentrations may be increased by VIRACEPT.
cyclosporine
tacrolimus
sirolimus
↑ immuno-suppressants
Inhaled beta agonist:
salmeterol
↑ salmeterol Concurrent administration of salmeterol with VIRACEPT is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Inhaled/nasal steroid: Fluticasone ↑ fluticasone Concomitant use of fluticasone propionate and VIRACEPT may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use.
Macrolide Antibiotic:
azithromycin

↑ azithromycin
Dose adjustment of azithromycin is not recommended, but close monitoring for known side effects such as liver enzyme abnormalities and hearing impairment is warranted.
Narcotic Analgesic: Dosage of methadone may need to be increased when coadministered with VIRACEPT.
methadone ↓ methadone
Oral Contraceptive: Alternative or additional contraceptive measures should be used when oral contraceptives and VIRACEPT are coadministered.
ethinyl estradiol ↓ ethinyl estradiol
PDE5 Inhibitors:
sildenafil
vardenafil
tadalafil



↑ PDE5 Inhibitors
Concomitant use of PDE5 inhibitors and VIRACEPT should be undertaken with caution.

May result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism.
Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH):
Use of sildenafil (REVATIO) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) [see Contraindications]. The following dose adjustments are recommended for use of tadalafil (ADCIRCA™) with VIRACEPT: Coadministration of ADCIRCA in patients on VIRACEPT or coadministration of VIRACEPT in patients on ADCIRCA:
Start at or adjust ADCIRCA to 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.
Use of PDE5 inhibitors for erectile dysfunction:
Sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg in 24 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours, is recommended. Use with increased monitoring for adverse events.


Table name:
Drugs That Interfere with Hemostasis
Clinical Impact: Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of celecoxib with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ see Warnings and Precautions ( 5.11 ) ].
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ see Warnings and Precautions ( 5.2 ) ].
In two studies in healthy volunteers, and in patients with osteoarthritis and established heart disease respectively, celecoxib (200 to 400 mg daily) has demonstrated a lack of interference with the cardioprotective antiplatelet effect of aspirin (100 to 325 mg).
Intervention: Concomitant use of celecoxib and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions ( 5.11 ) ].
Celecoxib is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, coadministration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: During concomitant use of celecoxib and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of celecoxib and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ see Warnings and Precautions ( 5.6 ) ]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as postmarketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of celecoxib with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ see Warnings and Precautions ( 5.6 ) ].
Digoxin
Clinical Impact: The concomitant use of Celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of celecoxib and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of celecoxib and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Celecoxib has no effect on methotrexate pharmacokinetics.
Intervention: During concomitant use of celecoxib and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of celecoxib and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of celecoxib and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of Celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ see Warnings and Precautions ( 5.2 ) ].
Intervention: The concomitant use of Celecoxib with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of celecoxib and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of celecoxib and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.
NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.
In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
CYP2C9 Inhibitors or inducers
Clinical Impact: Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Coadministration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may enhance the exposure and toxicity of celecoxib whereas coadministration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of celecoxib.
Intervention: Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers [ see Clinical Pharmacology ( 12.3 ) ].
CYP2D6 substrates
Clinical Impact: In vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6 (e.g. atomoxetine), and celecoxib may enhance the exposure and toxicity of these drugs.
Intervention: Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2D6 substrates [ see Clinical Pharmacology ( 12.3 ) ].
Corticosteroids
Clinical Impact: Concomitant use of corticosteroids with celecoxib may increase the risk of GI ulceration or bleeding.
Intervention: Monitor patients with concomitant use of celecoxib with corticosteroids for signs of bleeding [ see Warnings and Precautions ( 5.2 ) ].


Table name:
Inhibitors of CYP3A4
Clinical Impact: The concomitant use of Fentanyl Citrate Injection and CYP3A4 inhibitors can increase the plasma concentration of fentanyl, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of Fentanyl Citrate Injection is achieved [see Warnings and Precautions (5.3)].After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the fentanyl plasma concentration will decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to fentanyl.
Intervention: If concomitant use is necessary, consider dosage reduction of Fentanyl Citrate Injection until stable drug effects are achieved [see Dosage and Administration (2.1)]. Monitor patients for respiratory depression and sedation at frequent intervals.If a CYP3A4 inhibitor is discontinued, consider increasing the Fentanyl Citrate Injection dosage until stable drug effects are achieved.  Monitor for signs of opioid withdrawal.
Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir), grapefruit juice.
CYP3A4 Inducers
Clinical Impact: The concomitant use of Fentanyl Citrate Injection and CYP3A4 inducers can decrease the plasma concentration of fentanyl [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to fentanyl [see Warnings and Precautions (5.3)]. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the fentanyl plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.
Intervention: If concomitant use is necessary, consider increasing the Fentanyl Citrate Injection dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider Fentanyl Citrate Injection dosage reduction and monitor for signs of respiratory depression.
Examples: Rifampin, carbamazepine, phenytoin
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact: The concomitant use of Fentanyl Citrate Injection with CNS depressants my result in decreased pulmonary artery pressure and may cause hypotension.  Even small dosages of diazepam may cause cardiovascular depression when added to high dose or anesthetic dosages of Fentanyl Citrate Injection.  As postoperative analgesia, concomitant use of Fentanyl Citrate Injection can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention: As postoperative analgesia, start with a lower dose of Fentanyl Citrate Injection and monitor patients for signs of respiratory depression, sedation, and hypotension. Fluids or other measures to counter hypotension should be available [see Warnings and Precautions (5.4)].
Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, barbiturates, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Warnings and Precautions (5.7)].
Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Fentanyl Citrate Injection if serotonin syndrome is suspected.
Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue)..
Monoamine Oxidase Inhibitors
Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome [see Warnings and Precautions (5.7)] or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)]
Intervention: The use of Fentanyl Citrate Injection is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples: Phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact: May reduce the analgesic effect of Fentanyl Citrate Injection and/or precipitate withdrawal symptoms.
Intervention: Avoid concomitant use.
Examples: Butorphanol, nalbuphine, pentazocine, buprenorphine.
Muscle Relaxants
Clinical Impact: Fentanyl may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Diuretics
Clinical Impact:  Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when Fentanyl Citrate Injection is used concomitantly with anticholinergic drugs.
Neuroleptics
Clinical Impact: Elevated blood pressure, with and without pre-existing hypertension, has been reported following administration of Fentanyl Citrate Injection combined with a neuroleptic see Warnings and Precautions (5.13)].
Intervention: ECG monitoring is indicated when a neuroleptic agent is used in conjunction with Fentanyl Citrate Injection as an anesthetic premedication, for the induction of anesthesia, or as an adjunct in the maintenance of general or regional anesthesia.
Nitrous oxide
Clinical Impact: Nitrous oxide has been reported to produce cardiovascular depression when given with higher doses of Fentanyl Citrate Injection.
Intervention: Monitor patients for signs of cardiovascular depression that may be greater than otherwise expected.


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
 Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration  Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
 Drugs that may alter T 4 and T 3 metabolism
 Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.11, 7.3)


Table name:
Drugs That Interfere with Hemostasis
Clinical Impact: Indomethacin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of indomethacin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of indomethacin with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ see Warnings and Precautions ( 5.11 )].
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ see Warnings and Precautions ( 5.2 ) ].
Intervention: Concomitant use of indomethacin capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions ( 5.11 )].Indomethacin is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: During concomitant use of indomethacin capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.During concomitant use of indomethacin capsules and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ see Warnings and Precautions ( 5.6 )].When these drugs are administered concomitantly, patients should be adequately hydrated.  Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.It has been reported that the addition of triamterene to a maintenance schedule of Indomethacin resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin and triamterene should not be administered together.Both indomethacin and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently [ see Warnings and Precautions ( 5.6 )].  
Intervention: Indomethacin and triamterene should not be administered together. During concomitant use of indomethacin capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects. Be aware that indomethacin and potassium-sparing diuretics may both be associated with increased serum potassium levels. [ see Warnings and Precautions ( 5.6 )].  
Digoxin  
Clinical Impact: The concomitant use of indomethacin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.  
Intervention: During concomitant use of indomethacin capsules and digoxin, monitor serum digoxin levels.  
Lithium  
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.  
Intervention: During concomitant use of indomethacin capsules and lithium, monitor patients for signs of lithium toxicity.  
Methotrexate  
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).  
Intervention: During concomitant use of indomethacin capsules and methotrexate, monitor patients for methotrexate toxicity.  
Cyclosporine  
Clinical Impact: Concomitant use of indomethacin capsules and cyclosporine may increase cyclosporine's nephrotoxicity.  
Intervention: During concomitant use of indomethacin capsules and cyclosporine, monitor patients for signs of worsening renal function.  
NSAIDs and Salicylates  
Clinical Impact: Concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ see Warnings and Precautions ( 5.2 )]. Combined use with diflunisal may be particularly hazardous because diflunisal causes significantly higher plasma levels of indomethacin [see Clinical Pharmacology ( 12.3 )].In some patients, combined use of indomethacin and diflunisal has been associated with fatal gastrointestinal hemorrhage.  
Intervention: The concomitant use of indomethacin with other NSAIDs or salicylates, especially diflunisal, is not recommended.  
Pemetrexed  
Clinical Impact: Concomitant use of indomethacin capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).  
Intervention: During concomitant use of indomethacin capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.  
Probenecid  
Clinical Impact: When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased.  
Intervention: During the concomitant use of indomethacin and probenecid, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect.  When increases in the dose of indomethacin are made, they should be made carefully and in small increments.  


Table name:
Drug  Effect 
 Phenylephrine with prior administration of monoamine oxidase inhibitors (MAOI).  Cardiac pressor response potentiated. May cause acute hypertensive crisis.
 Phenylephrine with tricyclic antidepressants.  Pressor response increased.
 Phenylephrine with ergot alkaloids.  Excessive rise in blood pressure.
 Phenylephrine with bronchodilator sympathomimetic agents and with epinephrine or other sympathomimetics.  Tachycardia or other arrhythmias may occur.
 Phenylephrine with prior administration of propranolol or other β-adrenergic blockers.  Cardiostimulating effects blocked.
 Phenylephrine with atropine sulfate.  Reflex bradycardia blocked; pressor response enhanced.
 Phenylephrine with prior administration of phentolamine or other α-adrenergic blockers.  Pressor response decreased.
 Phenylephrine with diet preparations, such as amphetamines or phenylpropanolamine.  Synergistic adrenergic response.


Table name:
Table 11 Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies (see CLINICAL PHARMACOLOGY, for Magnitude of Interaction, Tables 6 and 7)
Concomitant Drug Class: Drug Name Effect on Concentration Clinical Comment
HIV-Antiviral Agents
Protease Inhibitors: Appropriate doses for these combinations, with respect to safety and efficacy, have not been established.
indinavir ↑ nelfinavir
↑ indinavir
ritonavir ↑ nelfinavir
saquinavir ↑ saquinavir
Non-nucleoside Reverse Transcriptase Inhibitors: Appropriate doses for these combinations, with respect to safety and efficacy, have not been established.
delavirdine ↑ nelfinavir
↓ delavirdine
nevirapine ↓ nelfinavir (Cmin)
Nucleoside Reverse Transcriptase Inhibitor:
didanosine
It is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after VIRACEPT (given with food).
Other Agents
Anti-Convulsants: May decrease nelfinavir plasma concentrations. VIRACEPT may not be effective due to decreased nelfinavir plasma concentrations in patients taking these agents concomitantly.
carbamazepine
phenobarbital
↓ nelfinavir
Anti-Convulsant: Phenytoin plasma/serum concentrations should be monitored; phenytoin dose may require adjustment to compensate for altered phenytoin concentration.
phenytoin ↓ phenytoin
Anti-Mycobacterial: It is recommended that the dose of rifabutin be reduced to one-half the usual dose when administered with VIRACEPT; 1250 mg BID is the preferred dose of VIRACEPT when coadministered with rifabutin.
rifabutin ↑ rifabutin
↓ nelfinavir
  (750 mg TID)
↔ nelfinavir
  (1250 mg BID)
PDE5 Inhibitors:
sildenafil
vardenafil
tadalafil
↑ PDE5 Inhibitors Concomitant use of PDE5 inhibitors and VIRACEPT should be undertaken with caution. If concomitant use of PDE5 inhibitors and VIRACEPT is required, sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg in 72 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours, is recommended.
HMG-CoA Reductase Inhibitor: Use lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin or fluvastatin in combination with VIRACEPT.
atorvastatin ↑ atorvastatin
rosuvastatin ↑ rosuvastatin
Immuno-suppressants: Plasma concentrations may be increased by VIRACEPT.
cyclosporine
tacrolimus
sirolimus
↑ immuno-suppressants
Narcotic Analgesic: Dosage of methadone may need to be increased when coadministered with VIRACEPT.
methadone ↓ methadone
Oral Contraceptive: Alternative or additional contraceptive measures should be used when oral contraceptives and VIRACEPT are coadministered.
ethinyl estradiol ↓ ethinyl estradiol
Macrolide Antibiotic:
azithromycin

↑ azithromycin
Dose adjustment of azithromycin is not recommended, but close monitoring for known side effects such as liver enzyme abnormalities and hearing impairment is warranted.
Inhaled/nasal steroid: Fluticasone ↑ fluticasone Concomitant use of fluticasone propionate and VIRACEPT may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use.
Antidepressant: trazodone ↑ trazodone Concomitant use of trazodone and VIRACEPT may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as VIRACEPT, the combination should be used with caution and a lower dose of trazodone should be considered.


Table name:
Table 5 Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or on Predicted Interaction with INVIRASE/ritonavir
Concomitant Drug Class:
Drug Name
Effect on Concentration of Saquinavir or Concomitant Drug Clinical Comment
HIV-Antiviral Agents
Non-nucleoside reverse transcriptase inhibitor:
DelavirdineINVIRASE/ritonavir interaction has not been evaluated.
↑ Saquinavir
 
Effect on delavirdine is not well established
Appropriate doses of the combination with respect to safety and efficacy have not been established.
Non-nucleoside reverse transcriptase inhibitor:
EfavirenzSee CLINICAL PHARMACOLOGY: Pharmacokinetics , Table 2 and Table 3 for magnitude of interactions.,
nevirapine
↓ Saquinavir
↔ Efavirenz
Appropriate doses of the combination of efavirenz or nevirapine and INVIRASE/ritonavir (1000/100 mg bid) with respect to safety and efficacy have not been established.
HIV protease inhibitor:
Atazanavir
INVIRASE/ritonavir
↑ Saquinavir
↑ Ritonavir
↔ Atazanavir
Appropriate dosing recommendations for this combination, with respect to efficacy and safety, have not been established. When 1600 mg INVIRASE/100 mg ritonavir and 300 mg atazanavir were coadministered, plasma concentrations of saquinavir and ritonavir were increased.
HIV protease inhibitor:
Indinavir
↑ Saquinavir
 
Effect on indinavir is not well established
Appropriate doses of the combination of indinavir and INVIRASE/ritonavir with respect to safety and efficacy have not been established.
HIV protease inhibitor:
Lopinavir/ritonavir (coformulated capsule)
↔ Saquinavir
↔ Lopinavir
↓ Ritonavir
Evidence from several clinical trials indicates that saquinavir concentrations achieved with the saquinavir and lopinavir/ritonavir combination are similar to those achieved following saquinavir/ritonavir 1000/100 mg. The recommended dose for this combination is saquinavir 1000 mg plus lopinavir/ritonavir 400/100 mg bid.
HIV protease inhibitor:
Tipranavir/ritonavir
↓ Saquinavir Combining saquinavir with tipranavir/ritonavir is not recommended.
HIV fusion inhibitor:
Enfuvirtide
Saquinavir soft gel capsules/ritonavir
↔ enfuvirtide
No clinically significant interaction was noted from a study in 12 HIV patients who received enfuvirtide concomitantly with saquinavir soft gel capsules/ritonavir 1000/100 mg bid. No dose adjustments are required.
Other Agents
Antiarrhythmics:
Lidocaine (systemic)
↑ Antiarrhythmics Caution is warranted and therapeutic concentration monitoring, if available, is recommended for antiarrhythmics given with INVIRASE/ritonavir.
Anticoagulant:
Warfarin
↑ Warfarin Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants:
Carbamazepine, phenobarbital, phenytoin
↓ Saquinavir
 
Effect on carbamazepine, phenobarbital, and phenytoin is not well established
Use with caution, saquinavir may be less effective due to decreased saquinavir plasma concentrations in patients taking these agents concomitantly.
Anti-infective:
Clarithromycin
↑ Saquinavir
↑ Clarithromycin
Appropriate doses of the combination of clarithromycin and INVIRASE/ritonavir with respect to safety and efficacy have not been established.
 
Due to the known effect of ritonavir on clarithromycin concentrations, the following dose adjustments are recommended:
For patients with renal impairment, the following dosage adjustments should be considered:
  For patients with CLCR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients with CLCR <30 mL/min the dose of clarithromycin should be decreased by 75%. No dose adjustment for patients with normal renal function is necessary.
Antifungal:
Ketoconazole, itraconazole
↔ Saquinavir
↔ Ritonavir
↑ Ketoconazole
Appropriate doses of the combination of ketoconazole or itraconazole and INVIRASE/ritonavir with respect to safety and efficacy have not been established. When INVIRASE/ritonavir and ketoconazole are coadministered, plasma concentration of ketoconazole was increased (see Table 2 ). Hence, doses of ketoconazole > 200 mg/day are not recommended.
Antimycobacterial:
Rifabutin
↓ Saquinavir
↑ Rifabutin
Appropriate doses of the combination of rifabutin and INVIRASE/ritonavir with respect to safety and efficacy have not been established.
Benzodiazepines:
Alprazolam, clorazepate, diazepam, flurazepam
↑ Benzodiazepines Clinical significance is unknown; however, a decrease in benzodiazepine dose may be needed.
Benzodiazepine :
Intravenously administered Midazolam
↑ Midazolam Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, INVIRASE should not be given with orally administered midazolam [see Contraindications (4)]. If INVIRASE is coadministered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.
Calcium channel blockers :
Diltiazem, felodipine, nifedipine, nicardipine, nimodipine, verapamil, amlodipine, nisoldipine, isradipine
↑ Calcium channel blockers Caution is warranted and clinical monitoring of patients is recommended.
Corticosteroid:
Dexamethasone
↓ Saquinavir Use with caution, saquinavir may be less effective due to decreased saquinavir plasma concentrations in patients taking these agents concomitantly.
Digitalis Glycosides:
Digoxin
↑ Digoxin
 
Increases in serum digoxin concentration were greater in female subjects as compared to male subjects when digoxin was coadministered with INVIRASE/ritonavir.
Concomitant use of INVIRASE/ritonavir with digoxin results in a significant increase in serum concentrations of digoxin. Caution should be exercised when INVIRASE/ritonavir and digoxin are coadministered; serum digoxin concentrations should be monitored and the dose of digoxin may need to be reduced when coadministered with INVIRASE/ritonavir (see WARNINGS ).
Inhaled/nasal steroid:
Fluticasone
INVIRASE/ritonavir
↑ Fluticasone
Concomitant use of fluticasone propionate and INVIRASE/ritonavir may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Coadministration of fluticasone propionate and INVIRASE/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects (see WARNINGS ).
HMG-CoA reductase inhibitors :
Atorvastatin, rosuvastatin
↑ Atorvastatin
↑ Rosuvastatin
Use lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as fluvastatin in combination with Invirase/ritonavir (see WARNINGS ).
Immunosuppressants :
Cyclosporine, tacrolimus, rapamycin
↑ Immunosuppressants Therapeutic concentration monitoring is recommended for immunosuppressant agents when coadministered with INVIRASE/ritonavir.
Narcotic analgesic:
Methadone
↓ Methadone Dosage of methadone may need to be increased when coadministered with INVIRASE/ritonavir.
Oral contraceptives:
Ethinyl estradiol
↓ Ethinyl estradiol Alternative or additional contraceptive measures should be used when estrogen-based oral contraceptives and INVIRASE/ritonavir are coadministered.
PDE5 inhibitors (phosphodiesterase type 5 inhibitors):
Sildenafil, vardenafil, tadalafil
↑ Sildenafil
↔ Saquinavir
 
↑ Vardenafil
↑ Tadalafil
Use sildenafil with caution at reduced doses of 25 mg every 48 hours with increased monitoring of adverse events when administered concomitantly with INVIRASE/ritonavir.
 
Use vardenafil with caution at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring of adverse events when administered concomitantly with INVIRASE/ritonavir.
 
Use tadalafil with caution at reduced doses of no more than 10 mg every 72 hours with increased monitoring of adverse events when administered concomitantly with INVIRASE/ritonavir.
Antidepressant:
Trazodone
↑ Trazodone Concomitant use of trazodone and INVIRASE/ritonavir may increase plasma concentration of trazodone. Adverse events of nausea, dizziness, hypotension and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as INVIRASE/ritonavir, the combination should be used with caution and lower dose of trazodone should be considered.
Tricyclic antidepressants : Amitriptyline, imipramine ↑ Tricyclics Therapeutic concentration monitoring is recommended for tricyclic antidepressants when coadministered with INVIRASE/ritonavir.
Proton pump inhibitors: Omeprazole ↑ Saquinavir When INVIRASE/ritonavir is co-administered with omeprazole, saquinavir concentrations are increased significantly. If omeprazole or another proton pump inhibitor is taken concomitantly with INVIRASE/ritonavir, caution is advised and monitoring for potential saquinavir toxicities is recommended, particularly gastrointestinal symptoms, increased triglycerides, and deep vein thrombosis.
Herbal Products:
St. John's wort (hypericum perforatum)
↓ Saquinavir Coadministration may lead to loss of virologic response and possible resistance to INVIRASE or to the class of protease inhibitors (see WARNINGS ).
Garlic Capsules ↓ Saquinavir Coadministration of garlic capsules and saquinavir is not recommended due to the potential for garlic capsules to induce the metabolism of saquinavir which may result in sub-therapeutic saquinavir concentrations.


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine / Dopamine Agonists Glucocorticoids Octreotide Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( > 1 µg/kg/min); Glucocorticoids (hydrocortisone > 100 mg/day or equivalent); Octreotide ( > 100 µg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T 4 and T 3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) Administration of these agents with levothyroxine results in an initial transient increase in FT 4. Continued administration results in a decrease in serum T 4 and normal FT 4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T 4 and T 3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT 4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T 4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T 4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5’-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone > 4 mg/day) Propylthiouracil (PTU) Administration of these enzyme inhibitors decreases the peripheral conversion of T 4 to T 3, leading to decreased T 3 levels. However, serum T 4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T 3 and T 4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T 3 concentrations by 30% with minimal change in serum T 4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T 3 and T 4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Growth Hormones - Somatrem - Somatropin Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline) Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.


Table name:
Drug Interactions Associated with Increased Risk of  Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice Avoid grapefruit juice


Table name:
Table 3 Clinically Significant Drug Interactions with Meloxicam
Drugs  that  Interfere  with  Hemostasis
Clinical  Impact :
Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.
Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. 
Intervention
Monitor patients with concomitant use of meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see  Warnings  and  Precautions  ( 5 . 11)]. 
Aspirin 
Clinical  Impact
Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see  Warnings  and  Precautions  ( 5 . 2)]. 
Intervention
Concomitant use of meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see  Warnings  and  Precautions  ( 5 . 11)]. 

Meloxicam is not a substitute for low dose aspirin for cardiovascular protection. 
ACE  Inhibitors Angiotensin  Receptor  Blockers or  Beta - Blockers 
Clinical  Impact

NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). 
In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. 
Intervention

During concomitant use of meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. 
During concomitant use of meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see  Warnings  and  Precautions  ( 5 . 6)]. 
When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. 
Diuretics 

Clinical  Impact

Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. 
Intervention

During concomitant use of meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see  Warnings  and  Precautions  ( 5 . 6)]. 
Lithium 
Clinical  Impact

NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [see  Clinical  Pharmacology  ( 12 . 3)]. 
Intervention

During concomitant use of meloxicam and lithium, monitor patients for signs of lithium toxicity. 
Methotrexate 
Clinical  Impact

Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention

During concomitant use of meloxicam and methotrexate, monitor patients for methotrexate toxicity. 
Cyclosporine 

Clinical  Impact

Concomitant use of meloxicam and cyclosporine may increase cyclosporine’s nephrotoxicity. 
Intervention

During concomitant use of meloxicam and cyclosporine, monitor patients for signs of worsening renal function. 
NSAIDs  and  Salicylates 

Clinical  Impact

Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see  Warnings  and  Precautions  ( 5 . 2)]. 
Intervention

The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended. 
Pemetrexed 

Clinical  Impact

Concomitant use of meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). 
Intervention

During concomitant use of meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended. 


Table name:
Table 2: Drug-Thyroidal Axis Interactions
  Drug or Drug Class   Effect
  Drugs that may reduce TSH secretion–the reduction is not sustained; therefore, hypothyroidism does not occur
  Dopamine / Dopamine Agonists
Glucocorticoids
Octreotide
  Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day).
  Drugs that alter thyroid hormone secretion
  Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
  Aminoglutethimide
Amiodarone
Iodide(including iodine-containing
  Radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
  Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients.  The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
  Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
  Amiodarone
Iodide(including iodine-containing   
  Radiographic contrast agents)
  Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma).  Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
  Drugs that may decrease T4 absorption, which may result in hypothyroidism
  Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
  Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism.  Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents.  Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
  Drugs that may alter T4 and T3 serum transport  - but FT4 concentration remains normal; and, therefore, the patient remains euthyroid
  Drugs that may increase serum TBG concentration   Drugs that may decrease serum TBG concentration
  Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
  Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
  Drugs that may cause protein-binding site displacement
  Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
  Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4, and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
  Drugs that may alter T4 and T3 metabolism
  Drugs that may increase hepatic metabolism, which may result  in hypothyroidism
  Carbamazepine
Hydantoins
Phenobarbital
Rifampin
  Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
  Drugs that may decrease T4 5’-deiodinase activity
  Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
  Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4  levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
  Miscellaneous
  Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
  Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
  Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors
  (SSRIs; e.g., Sertraline)
  Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of  tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
  Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
  Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
  Cardiac Glycosides   Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
  Cytokines
- Interferon-α
- Interleukin-2
  Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
  Growth Hormones
- Somatrem
- Somatropin
  Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
  Ketamine   Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
  Methylxanthine Bronchodilators
- (e.g., Theophylline)
  Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
  Radiographic Agents   Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
  Sympathomimetics   Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
  Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
  These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.


Table name:
Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme
Inhibitors
Inducers
CYP2C9 
amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast
aprepitant, bosentan, carbamazepine, phenobarbital, rifampin 
CYP1A2 
acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton
montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking 
CYP3A4 
alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton
armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide 


Table name:
Interacting Drug Interaction
Theophylline Serious and fatal reactions. Avoid concomitant use. Monitor serum level ( 7)
Warfarin Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding ( 7)
Antidiabetic agents Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose ( 7)
Phenytoin Monitor phenytoin level ( 7)
Methotrexate Monitor for methotrexate toxicity ( 7)
Cyclosporine May increase serum creatinine. Monitor serum creatinine ( 7)
Multivalent cation-containing products including antacids, metal cations or didanosine Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin ( 7)


Table name:
Inhibitors of CYP2D6
Clinical Impact:
The concomitant use of tramadol hydrochloride extended-release tablets and CYP2D6 inhibitors may result in an increase in the plasma concentration of tramadol and a decrease in the plasma concentration of M1, particularly when an inhibitor is added after a stable dose of tramadol hydrochloride extended-release tablets is achieved. Since M1 is a more potent µ-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome.

After stopping a CYP2D6 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease and the M1 plasma concentration will increase which could increase or prolong therapeutic effects but also increase adverse reactions related to opioid toxicity, and may cause potentially fatal respiratory depression [see Clinical Pharmacology (12.3)].
Intervention:
If concomitant use of a CYP2D6 inhibitor is necessary, follow patients closely for adverse reactions including opioid withdrawal, seizures, and serotonin syndrome.

If a CYP2D6 inhibitor is discontinued, consider lowering tramadol hydrochloride extended-release tablets dosage until stable drug effects are achieved. Follow patients closely for adverse events including respiratory depression and sedation.
Examples
Quinidine, fluoxetine, paroxetine and bupropion
Inhibitors of CYP3A4
Clinical Impact:
The concomitant use of tramadol hydrochloride extended-release tablets and CYP3A4 inhibitors can increase the plasma concentration of tramadol and may result in a greater amount of metabolism via CYP2D6 and greater levels of M1. Follow patients closely for increased risk of serious adverse events including seizures and serotonin syndrome, and adverse reactions related to opioid toxicity including potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of tramadol hydrochloride extended-release tablets is achieved.

After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy and possibly signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol.
Intervention:
If concomitant use is necessary, consider dosage reduction of tramadol hydrochloride extended-release tablets until stable drug effects are achieved. Follow patients closely for seizures and serotonin syndrome, and signs of respiratory depression and sedation at frequent intervals.
If a CYP3A4 inhibitor is discontinued, consider increasing the tramadol hydrochloride extended-release tablets dosage until stable drug effects are achieved and follow patients for signs and symptoms of opioid withdrawal.
Examples
Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)
CYP3A4 Inducers
Clinical Impact:
The concomitant use of tramadol hydrochloride extended-release tablets and CYP3A4 inducers can decrease the plasma concentration of tramadol [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to tramadol, [see Warnings and Precautions (5.5)].
After stopping a CYP3A4 inducer, as the effects of the inducer decline, the tramadol plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause seizures and serotonin syndrome, and potentially fatal respiratory depression.
Intervention:
If concomitant use is necessary, consider increasing the tramadol hydrochloride extended-release tablets dosage until stable drug effects are achieved. Follow patients for signs of opioid withdrawal.
If a CYP3A4 inducer is discontinued, consider tramadol hydrochloride extended-release tablets dosage reduction and monitor for seizures and serotonin syndrome, and signs of sedation and respiratory depression.

Patients taking carbamazepine, a CYP3A4 inducer, may have a significantly reduced analgesic effect of tramadol. Because carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of tramadol hydrochloride extended-release tablets and carbamazepine is not recommended.
Examples:
Rifampin, carbamazepine, phenytoin
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact:
Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:
Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.6)].
Examples:
Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact:
The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention:
If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue tramadol hydrochloride extended-release tablets if serotonin syndrome is suspected.
Examples:
Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:
MAOI interactions with opioids may manifest as serotonin syndrome [see Warnings and Precautions (5.7)] or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)].
Intervention:
Do not use tramadol hydrochloride extended-release tablets in patients taking MAOIs or within 14 days of stopping such treatment.
Examples:
phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:
May reduce the analgesic effect of tramadol hydrochloride extended-release tablets and/or precipitate withdrawal symptoms.
Intervention:
Avoid concomitant use.
Examples:
butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact:
Tramadol may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:
Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of tramadol hydrochloride extended-release tablets and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact:
Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:
Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:
The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:
Monitor patients for signs of urinary retention or reduced gastric motility when tramadol hydrochloride extended-release tablets are used concomitantly with anticholinergic drugs.
Digoxin
Clinical Impact:
Post-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity.
Intervention:
Follow patients for signs of digoxin toxicity and adjust the dosage of digoxin as needed.
Warfarin
Clinical Impact:
Post-marketing surveillance of tramadol has revealed rare reports of alteration of warfarin effect, including elevation of prothrombin times.
Intervention:
Monitor the prothrombin time of patients on warfarin for signs of an interaction and adjust the dosage of warfarin as needed.


Table name:
Increased Risk of Myopathy/Rhabdomyolysis (2, 5.1, 7, 12.3)
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
Lopinavir plus ritonavir Use lowest dose necessary
Clarithromycin, itraconazole,
HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)
Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) Do not exceed 40 mg atorvastatin daily


Table name:
Table 18. Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug Dosing Schedule Effect on Active Moiety (Risperidone + 9-Hydroxy- Risperidone (RatioChange relative to reference) Risperidone Dose Recommendation
Coadministered Drug Risperidone AUC Cmax
Enzyme (CYP2D6) Inhibitors
Fluoxetine 20 mg/day 2 or 3 mg twice daily 1.4 1.5 Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine 10 mg/day 4 mg/day 1.3 - Re-evaluate dosing. Do not exceed 8 mg/day
20 mg/day 4 mg/day 1.6 -
40 mg/day 4 mg/day 1.8 -
Enzyme (CYP3A/PgP inducers) Inducers
Carbamazepine 573 ± 168 mg/day 3 mg twice daily 0.51 0.55 Titrate dose upwards. Do not exceed twice the patient's usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine 150 mg twice daily 1 mg single dose 1.2 1.4 Dose adjustment not needed
Cimetidine 400 mg twice daily 1 mg single dose 1.1 1.3 Dose adjustment not needed
Erythromycin 500 mg four times daily 1 mg single dose 1.1 0.94 Dose adjustment not needed
Other Drugs
Amitriptyline 50 mg twice daily 3 mg twice daily 1.2 1.1 Dose adjustment not needed


Table name:
Factors Dosage Adjustments for Aripiprazole
Known CYP2D6 Poor Metabolizers Administer half of usual dose
Known CYP2D6 Poor Metabolizersand strong CYP3A4 inhibitors Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors Administer half of usual dose
Strong CYP2D6 and CYP3A4inhibitors Administer a quarter of usual dose
Strong CYP3A4 inducers Double usual dose over 1 to 2 weeks


Table name:
Table 5 Effects on steady-state fexofenadine pharmacokinetics after 7 days of co-administration with fexofenadine hydrochloride 120 mg every 12 hours in healthy adult subjects (n=24)
Concomitant Drug CmaxSS
(Peak plasma concentration)
AUCss(0–12h)
(Extent of systemic exposure)
Erythromycin
(500 mg every 8 hrs)
+82% +109%
  
Ketoconazole
(400 mg once daily)
+135% +164%


Table name:
Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin Tablets, USP
Drug(s) Recommendation Comments
Tizanidine Contraindicated Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [ see Contraindications ( 4.2 )]
Theophylline Avoid Use
(Plasma Exposure Likely to be Increased and Prolonged)
Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate. [See Warnings and Precautions ( 5.6 ).]
Drugs Known to Prolong QT Interval Avoid Use Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions ( 5.10 ) and Use in
Specific Populations ( 8.5 )].
Oral antidiabetic drugs Use with caution Glucose-lowering effect potentiated Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs. [See Adverse Reactions ( 6.1).]
Phenytoin Use with caution Altered serum levels of phenytoin (increased and decreased) To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin with phenytoin.
Cyclosporine Use with caution (transient elevations in serum creatinine) Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs Use with caution (Increase in anticoagulant effect) The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole Use with caution Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin [see Warnings and Precautions ( 5.15)].
Clozapine Use with caution Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs Use with caution Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil Use with caution Two-fold increase in exposure Monitor for sildenafil toxicity (see Pharmacokinetics  12.3).
Duloxetine Avoid Use
Five-fold increase in duloxetine exposure
If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin Tablets, USP
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx®
(didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)
Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration. ( 2 )].
Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid
Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)
Potentiation of ciprofloxacin toxicity may occur.


Table name:
Drugs That May Potentiate Renal Dysfunction
Antibiotics Antineoplastics Anti-inflammatory Drugs Gastrointestinal Agents
ciprofloxacin gentamicin tobramycin vancomycin trimethoprim with sulfamethoxazole     melphalan   azapropazon colchicine diclofenac naproxen sulindac       cimetidine ranitidine  
Antifungals
amphotericin B ketoconazole   Immunosuppressives
tacrolimus  
Other Drugs
fibric acid derivatives (e.g., bezafibrate, fenofibrate) methotrexate


Table name:
 Antiretrovirals
Clinical Impact:   The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known.
• Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology (12.3)].
• Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see Clinical Pharmacology (12.3)].
• There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole.
Intervention:   Rilpivirine-containing products: Concomitant use with omeprazole is contraindicated [see Contraindications (4)].
Atazanavir: Avoid concomitant use with omeprazole. See prescribing information for atazanavir for dosing information.
Nelfinavir: Avoid concomitant use with omeprazole. See prescribing information for nelfinavir.
Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities.
Other antiretrovirals: See prescribing information for specific antiretroviral drugs.
 Warfarin
Clinical Impact:   Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.  
Intervention:   Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range.  
 Methotrexate
Clinical Impact:   Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions (5.11)].
Intervention:   A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate.
 CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam)
 Clopidogrel
Clinical Impact:   Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology (12.3)].
There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel.
Intervention:   Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy [see Warnings and Precautions (5.6)].
Citalopram
Clinical Impact: Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology (12.3)].
Intervention:   Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.
Cilostazol
Clinical Impact: Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology (12.3)].
Intervention:   Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.
Phenytoin
Clinical Impact: Potential for increased exposure of phenytoin.
Intervention:   Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin.
Diazepam
Clinical Impact:   Increased exposure of diazepam [see Clinical Pharmacology (12.3)].
Intervention:   Monitor patients for increased sedation and reduce the dose of diazepam as needed.
Digoxin
Clinical Impact:   Potential for increased exposure of digoxin [see Clinical Pharmacology (12.3)].
Intervention:   Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information.  
 Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)
Clinical Impact:   Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
Intervention:   Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF [see Clinical Pharmacology (12.3)]. See the prescribing information for other drugs dependent on gastric pH for absorption.
 Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact:   Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions.
Intervention:   See Contraindications, Warnings and Precautions in prescribing information for clarithromycin. See Drug Interactions in prescribing information for amoxicillin.
 Tacrolimus
Clinical Impact:   Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.
Intervention:   Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
 Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact:   Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions (5.10),Clinical Pharmacology (12.2)].
Intervention:   Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
Interaction with Secretin Stimulation Test  
Clinical Impact:   Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention:   Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology (12.2)].
False Positive Urine Tests for THC
Clinical Impact:   There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.
Intervention:   An alternative confirmatory method should be considered to verify positive results.
Other
Clinical Impact:   There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram).
Intervention:   Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole.


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may
result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-
   containing radiographic
   contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which
may result in hyperthyroidism
Amiodarone
Iodide (including iodine-
containing Radiographic
contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase Drugs that may decrease
serum TBG concentration serum TBG concentration
Clofibrate Androgens / Anabolic Steroids
Estrogen-containing oral Asparaginase
   contraceptives Glucocorticoids
Estrogens (oral) Slow-Release Nicotinic Acid
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal
Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake
Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
NITROPRUSSIDE
Para-aminosalicylate sodium
Perphenazine
Resorcinol
 (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Drug Description of Interaction
Tolbutamide; Sulfonylureas Hypoglycemia potentiated
Methotrexate Decreases tubular reabsorption; clinical toxicity from methotrexate can result
Oral Anticoagulant Increased bleeding


Table name:
Table 3Drugs that Can Increase the Risk of Bleeding
 Drug  Class
 Specific  Drugs
 Anticoagulants 
 argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin 
 Antiplatelet Agents 
 aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine 
 Nonsteroidal Anti-Inflammatory Agents 
 celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac 
 Serotonin Reuptake Inhibitors 
 citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone 


Table name:
edema
hereditary coumarin resistance
hyperlipemia
hypothyroidism
nephrotic syndrome


Table name:
AED  Co - administered
AED  Concentration
Topiramate  Concentration
Phenytoin
NCor25%increase a
48%decrease
Carbamazepine(CBZ)
NC
40%decrease
CBZepoxide b
NC 
            NE
Valproic acid
11%decrease
14%decrease
Phenobarbital
NC
            NE
Primidone
NC
           NE
Lamotrigine
NCatTPM dosesupto400  mg/day 
         13%decrease


Table name:
Table 4: Clinically Relevant Interactions Affecting Omeprazole When Co-Administered with Other Drugs
CYP2C19 or CYP3A4 Inducers
Clinical Impact:
Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology (12.3)].
Intervention:
St. John’s Wort, rifampin: Avoid concomitant use with omeprazole [see Warnings and Precautions (5.9)].
Ritonavir-containing products: see prescribing information for specific drugs.
CYP2C19 or CYP3A4 Inhibitors
Clinical Impact:
Increased exposure of omeprazole [see Clinical Pharmacology (12.3)].
Intervention:
Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered.
 
See prescribing information for voriconazole.


Table name:
Interacting Drug Interaction
Theophylline Serious and fatal reactions. Avoid concomitant use. Monitor serum level ( 7)
Warfarin Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding ( 7)
Antidiabetic agents Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose ( 7)
Phenytoin Monitor phenytoin level ( 7)
Methotrexate Monitor for methotrexate toxicity ( 7)
Cyclosporine May increase serum creatinine. Monitor serum creatinine ( 7)
Multivalent cation-containing products including antacids, metal cations or didanosine Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin ( 7)


Table name:
 Interacting Agents  Prescribing Recommendations 
 Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone  Avoid simvastatin 
 Gemfibrozil, cyclosporine,danazol   Do not exceed 10 mg simvastatindaily 
 Amiodarone, verapamil  Do not exceed 20 mg simvastatin daily 
 Diltiazem  Do not exceed 40 mg simvastatin daily
 Grapefruit juice  Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on
Concentration of Lamotrigine or Concomitant Drug
Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine Decreased lamotrigine concentrations approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? carbamazepine epoxide May increase carbamazepine epoxide levels.
 Lopinavir/ritonavir ↓ lamotrigine Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir ↓ lamotrigine Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine
Increased lamotrigine concentrations slightly more than 2-fold.
? valproate There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.


Table name:
Table 5. Established Drug Interactions Based on Drug Interaction Trials
Concomitant Drug Class: Drug Name Effect on Concentration Clinical Comments
ANGIOTENSIN RECEPTOR BLOCKERS e.g.
valsartan*
losartan*
candesartan*
↑ angiotensin receptor blockers Decrease the dose of the angiotensin receptor blockers and monitor patients for signs and symptoms of hypotension and/or worsening renal function. If such events occur, consider further dose reduction of the angiotensin receptor blocker or switching to an alternative to the angiotensin receptor blocker.
ANTIARRHYTHMICS
amiodarone*,
bepridil*,
disopyramide*,
flecainide*,
lidocaine (systemic)*,
mexiletine*,
propafenone*,
quinidine*
↑ antiarrhythmics For contraindicated antiarrhythmics [see Contraindications (4)].

Therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with VIEKIRA PAK.
ANTIDIABETIC DRUGS
metformin ↔ metformin Monitor for signs of onset of lactic acidosis such as respiratory distress, somnolence, and non-specific abdominal distress or worsening renal function. Concomitant metformin use in patients with renal insufficiency or hepatic impairment is not recommended. Refer to the prescribing information of metformin for further guidance.
ANTIFUNGALS
ketoconazole ↑ ketoconazole When VIEKIRA PAK is co-administered with ketoconazole, the maximum daily dose of ketoconazole should be limited to 200 mg per day.
voriconazole* ↓ voriconazole Co-administration of VIEKIRA PAK with voriconazole is not recommended unless an assessment of the benefit-to-risk ratio justifies the use of voriconazole.
ANTIPSYCHOTICS
quetiapine* ↑ quetiapine For contraindicated antipsychotics [see Contraindications (4)].

Initiation of VIEKIRA PAK in patients taking quetiapine: Consider alternative anti-HCV therapy to avoid increases in quetiapine exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6th of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for the recommendations on adverse reaction monitoring. Initiation of quetiapine in patients taking VIEKIRA PAK: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.
CALCIUM CHANNEL BLOCKERS
amlodipine
nifedipine*
diltiazem*
verapamil*
↑ calcium channel blockers Decrease the dose of the calcium channel blocker. The dose of amlodipine should be decreased by at least 50%. Clinical monitoring of patients is recommended for edema and/or signs and symptoms of hypotension. If such events occur, consider further dose reduction of the calcium channel blocker or switching to an alternative to the calcium channel blocker.
CORTICOSTEROIDS (INHALED/NASAL)
fluticasone* ↑ fluticasone Concomitant use of VIEKIRA PAK with inhaled or nasal fluticasone may reduce serum cortisol concentrations. Alternative corticosteroids should be considered, particularly for long term use.
DIURETICS
furosemide ↑ furosemide (Cmax) Clinical monitoring of patients is recommended and therapy should be individualized based on patient’s response.
HIV-ANTIVIRAL AGENTS
atazanavir/ritonavir
once daily
↑ paritaprevir When coadministered with VIEKIRA PAK, atazanavir 300 mg (without ritonavir) should only be given in the morning.
darunavir/ritonavir ↓ darunavir (Ctrough) Treatment naïve patients or treatment experienced patients with no darunavir associated substitutions:

Darunavir 800 mg once daily (without ritonavir) can be co-administered with VIEKIRA PAK.

Treatment experienced patients with at least one darunavir resistance associated substitution or with no baseline resistance information:

Co-administration of darunavir/ritonavir 600/100 mg twice daily with VIEKIRA PAK is not recommended.
lopinavir/ritonavir ↑ paritaprevir Co-administration of VIEKIRA PAK with lopinavir/ritonavir is not recommended.
rilpivirine ↑ rilpivirine For contraindicated non-nucleoside reverse transcriptase inhibitors [see Contraindications (4)].

Co-administration of VIEKIRA PAK with rilpivirine once daily is not recommended due to potential for QT interval prolongation with higher concentrations of rilpivirine.
HMG CoA REDUCTASE INHIBITORS
rosuvastatin ↑ rosuvastatin For contraindicated HMG-CoA Reductase Inhibitors [see Contraindications (4)].

When VIEKIRA PAK is co-administered with rosuvastatin, the dose of rosuvastatin should not exceed 10 mg per day.
pravastatin ↑ pravastatin When VIEKIRA PAK is co-administered with pravastatin, the dose of pravastatin should not exceed 40 mg per day.
IMMUNOSUPPRESSANTS
cyclosporine ↑ cyclosporine For contraindicated immunosuppressants [see Contraindications (4)].

When initiating therapy with VIEKIRA PAK, reduce cyclosporine dose to 1/5th of the patient’s current cyclosporine dose. Measure cyclosporine blood concentrations to determine subsequent dose modifications. Upon completion of VIEKIRA PAK therapy, the appropriate time to resume pre-VIEKIRA PAK dose of cyclosporine should be guided by assessment of cyclosporine blood concentrations. Frequent assessment of renal function and cyclosporine-related side effects is recommended.
LONG ACTING BETA-ADRENOCEPTOR AGONIST
salmeterol* ↑ salmeterol Concurrent administration of VIEKIRA PAK and salmeterol is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
MUSCLE RELAXANTS
carisoprodol ↓ carisoprodol
↔ mepobramate
(metabolite of carisoprodol)
Increase dose if clinically indicated.
cyclobenzaprine ↓cyclobenzaprine
↓norcyclobenzaprine
(metabolite of cyclobenzaprine)
Increase dose if clinically indicated.
NARCOTIC ANALGESICS
buprenorphine/
naloxone
↑ buprenorphine
↑ norbuprenorphine
(metabolite of buprenorphine)
Patients should be closely monitored for sedation and cognitive effects.
Acetaminophen/
hydrocodone
↑ hydrocodone
↔ acetaminophen
Reduce the dose of hydrocodone by 50% and monitor patients for respiratory depression and sedation at frequent intervals. Upon completion of VIEKIRA PAK therapy, adjust the hydrocodone dose and monitor for signs of opioid withdrawal.
PROTON PUMP INHIBITORS
omeprazole ↓ omeprazole Monitor patients for decreased efficacy of omeprazole. Consider increasing the omeprazole dose in patients whose symptoms are not well controlled; avoid use of more than 40 mg per day of omeprazole.
SEDATIVES/HYPNOTICS
alprazolam ↑ alprazolam For contraindicated Sedatives/Hypnotics [see Contraindications (4)].

Clinical monitoring of patients is recommended. A decrease in alprazolam dose can be considered based on clinical response.
diazepam ↓ diazepam
↓ nordiazepam
(metabolite of diazepam)
Increase dose if clinically indicated.
See Clinical Pharmacology, Tables 8 and 9 .
The direction of the arrow indicates the direction of the change in exposures (Cmax and AUC) (↑ = increase of more than 20%, ↓ = decrease of more than 20%, ↔ = no change or change less than 20%).
*not studied.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
 Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)  Avoid atorvastatin
 HIV protease inhibitor (lopinavir plus ritonavir)  Use with caution and lowest dose necessary
 Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)  Do not exceed 20 mg atorvastatin daily
 HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
 Do not exceed 40 mg atorvastatin daily


Table name:
 AED  Co - administered
 AED  Concentration
 Topiramate  Concentration
 Phenytoin
 NCor25%increasea
 48%decrease
 Carbamazepine(CBZ)
 NC
 40%decrease
 CBZepoxideb
 NC 
             NE
 Valproic acid
 11%decrease
 14%decrease
 Phenobarbital
 NC
             NE
 Primidone
 NC
            NE
 Lamotrigine
 NCatTPM dosesupto400  mg/day 
          13%decrease


Table name:
Interacting DrugInteracting Drug InteractionInteraction
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products ( 2.4, 7.1)
Warfarin
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( 7.2)
Antidiabetic agents
Carefully monitor blood glucose ( 5.12, 7.3)


Table name: AED CoadministeredAED ConcentrationTopiramate Concentration
   
 
   
Phenytoin NC or 25% increasePlasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. 48% decrease
Carbamazepine (CBZ) NC 40% decrease
CBZ epoxideIs not administered but is an active metabolite of carbamazepine. NC NE
Valproic acid 11% decrease 14% decrease
Phenobarbital NC NE
Primidone NC NE
Lamotrigine NC at TPM doses up to 400 mg/day 13% decrease


Table name:
Table 7 Summary of AED Interactions with Oxcarbazepine
AED Coadministered Dose of AED
(mg/day)
Oxcarbazepine Dose
(mg/day)
Influence of Oxcarbazepine on AED Concentration
(Mean Change, 90% Confidence Interval)
Influence of AED on MHD Concentration
(Mean Change, 90% Confidence Interval)
Carbamazepine 400-2000 900 ncnc denotes a mean change of less than 10% 40% decrease
[CI: 17% decrease, 57% decrease]
Phenobarbital 100-150 600-1800 14% increase
[CI: 2% increase, 24% increase]
25% decrease
[CI: 12% decrease, 51% decrease]
Phenytoin 250-500 600-1800
>1200-2400
nc , Pediatrics
up to 40% increaseMean increase in adults at high oxcarbazepine doses
[CI: 12% increase, 60% increase]
30% decrease
[CI: 3% decrease, 48% decrease]
Valproic acid 400-2800 600-1800 nc 18% decrease
[CI: 13% decrease, 40% decrease]


Table name:
Table 3Drugs that Can Increase the Risk of Bleeding
Drug  Class
Specific  Drugs
Anticoagulants 
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin 
Antiplatelet Agents 
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine 
Nonsteroidal Anti-Inflammatory Agents 
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac 
Serotonin Reuptake Inhibitors 
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone 


Table name:
Drugs That May Increase the Risk of Hypoglycemia
Drugs: Antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, propoxyphene, salicylates, somatostatin analogs (e.g., octreotide), and sulfonamide antibiotics
Intervention: Dose reductions and increased frequency of glucose monitoring may be required when XULTOPHY 100/3.6 is co-administered with these drugs.
Drugs That May Decrease the Blood Glucose Lowering Effect of XULTOPHY 100/3.6
Drugs: Atypical antipsychotics (e.g., olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones.
Intervention: Dose increases and increased frequency of glucose monitoring may be required when XULTOPHY 100/3.6 is co-administered with these drugs.
Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of XULTOPHY 100/3.6
Drugs: Alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia.
Intervention: Dose adjustment and increased frequency of glucose monitoring may be required when XULTOPHY 100/3.6 is co-administered with these drugs.
Drugs That May Blunt Signs and Symptoms of Hypoglycemia
Drugs: Beta-blockers, clonidine, guanethidine, and reserpine
Intervention: Increased frequency of glucose monitoring may be required when XULTOPHY 100/3.6 is co-administered with these drugs.


Table name:
Table 4 Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table 5 for Magnitude of Interaction.
* The interaction between VIRAMUNE and the drug was evaluated in a clinical study. All other drug interactions shown are predicted.
Drug Name Effect on Concentration of
Nevirapine or Concomitant Drug
Clinical Comment
HIV Antiviral Agents: Protease Inhibitors (PIs)
Atazanavir/Ritonavir*

↓ Atazanavir
↑ Nevirapine

Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures.

Fosamprenavir*

↓ Amprenavir
↑ Nevirapine

Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.

Fosamprenavir/Ritonavir*

↓ Amprenavir

↑ Nevirapine

No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied.

Indinavir*

↓ Indinavir

The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established.

Lopinavir/Ritonavir*

↓Lopinavir

Dosing in adult patients:

A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.

Dosing in pediatric patients:

Please refer to the Kaletra® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.

Nelfinavir*

↓Nelfinavir M8 Metabolite
↓Nelfinavir Cmin

The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established.

Saquinavir/ritonavir

The interaction between nevirapine and saquinavir/ritonavir has not been evaluated

The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.

HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz*

↓ Efavirenz

The appropriate doses of these combinations with respect to safety and efficacy have not been established.

Delavirdine
Etravirine
Rilpivirine

  Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial.

Hepatitis C Antiviral Agents
Boceprevir

Plasma concentrations of boceprevir may be decreased due to induction of CYP3A4/5 by nevirapine.

Nevirapine and boceprevir should not be coadministered because decreases in boceprevir plasma concentrations may result in a reduction in efficacy.

Telaprevir

Plasma concentrations of telaprevir may be decreased due to induction of CYP3A4 by nevirapine and plasma concentrations of nevirapine may be increased due to inhibition of CYP3A4 by telaprevir.

Nevirapine and telaprevir should not be coadministered because changes in plasma concentrations of nevirapine, telaprevir, or both may result in a reduction in telaprevir efficacy or an increase in nevirapine-associated adverse events.

Other Agents
Analgesics:    
Methadone*

↓ Methadone

Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.

Antiarrhythmics:    
Amiodarone, disopyramide, lidocaine

Plasma concentrations may be decreased.

Appropriate doses for this combination have not been established.

Antibiotics:    
Clarithromycin*

↓ Clarithromycin
↑ 14-OH clarithromycin

Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.

Rifabutin*

↑ Rifabutin

Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.

Rifampin*

↓ Nevirapine

Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.

Anticonvulsants:
Carbamazepine, clonazepam, ethosuximide


Plasma concentrations of nevirapine and the anticonvulsant may be decreased.


Use with caution and monitor virologic response and levels of anticonvulsants.

Antifungals:    
Fluconazole*

↑Nevirapine

Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events.

Ketoconazole*

↓ Ketoconazole

Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.

Itraconazole

↓ Itraconazole

Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug.

Antithrombotics:
Warfarin


Plasma concentrations may be increased.


Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.

Calcium channel blockers:
Diltiazem, nifedipine, verapamil


Plasma concentrations may be decreased.


Appropriate doses for these combinations have not been established.

Cancer chemotherapy:
Cyclophosphamide


Plasma concentrations may be decreased.


Appropriate doses for this combination have not been established.

Ergot alkaloids:
Ergotamine


Plasma concentrations may be decreased.


Appropriate doses for this combination have not been established.

Immunosuppressants:
Cyclosporine, tacrolimus, sirolimus


Plasma concentrations may be decreased.


Appropriate doses for these combinations have not been established.

Motility agents:
Cisapride


Plasma concentrations may be decreased.


Appropriate doses for this combination have not been established.

Opiate agonists:
Fentanyl


Plasma concentrations may be decreased.


Appropriate doses for this combination have not been established.

Oral contraceptives:    
Ethinyl estradiol and Norethindrone*

↓ Ethinyl estradiol
↓ Norethindrone

Despite lower ethinyl estradiol and norethindrone exposures when coadministered with nevirapine, literature reports suggest that nevirapine has no effect on pregnancy rates among HIV-infected women on combined oral contraceptives. When coadministered with VIRAMUNE, no dose adjustment of ethinyl estradiol or norethindrone is needed when used in combination for contraception.

When these oral contraceptives are used for hormonal regulation during VIRAMUNE therapy, the therapeutic effect of the hormonal therapy should be monitored.


Table name:
Table 3 Established and Other Potentially Significant This table is not all inclusive. Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
Concomitant Drug Class: Drug Name Effect Clinical Comment
HIV antiviral agents
Protease inhibitor:
  atazanavir
↓atazanavir
↑ tenofovir
Coadministration of atazanavir with ATRIPLA is not recommended. Coadministration of atazanavir with either efavirenz or tenofovir DF decreases plasma concentrations of atazanavir. The combined effect of efavirenz plus tenofovir DF on atazanavir plasma concentrations is not known. Also, atazanavir has been shown to increase tenofovir concentrations. There are insufficient data to support dosing recommendations for atazanavir or atazanavir/ritonavir in combination with ATRIPLA.
Protease inhibitor:
  fosamprenavir calcium
↓ amprenavir Fosamprenavir (unboosted): Appropriate doses of fosamprenavir and ATRIPLA with respect to safety and efficacy have not been established.

Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when ATRIPLA is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when ATRIPLA is administered with fosamprenavir plus ritonavir twice daily.
Protease inhibitor:
  indinavir
↓ indinavir The optimal dose of indinavir, when given in combination with efavirenz, is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to efavirenz.
Protease inhibitor:
  lopinavir/ritonavir
↓ lopinavir
↑ tenofovir
Do not use once daily administration of lopinavir/ritonavir. Dose increase of lopinavir/ritonavir is recommended for all patients when coadministered with efavirenz. Refer to the full prescribing information for lopinavir/ritonavir for guidance on coadministration with efavirenz- or tenofovir-containing regimens, such as ATRIPLA. Patients should be monitored for tenofovir-associated adverse reactions.
Protease inhibitor:
  ritonavir
↑ ritonavir
↑ efavirenz
When ritonavir 500 mg every 12 hours was coadministered with efavirenz 600 mg once daily, the combination was associated with a higher frequency of adverse clinical experiences (e.g., dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when ATRIPLA is used in combination with ritonavir.
Protease inhibitor:
  saquinavir
↓ saquinavir Appropriate doses of the combination of efavirenz and saquinavir/ritonavir with respect to safety and efficacy have not been established.
CCR5 co-receptor antagonist:
  maraviroc
↓ maraviroc Efavirenz decreases plasma concentrations of maraviroc. Refer to the full prescribing information for maraviroc for guidance on coadministration with ATRIPLA.
NRTI:
  didanosine
↑ didanosine Coadministration of ATRIPLA and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse reactions including pancreatitis, lactic acidosis, and neuropathy. A dose reduction of didanosine is recommended when coadministered with tenofovir DF. For additional information on coadministration with tenofovir DF-containing products, please refer to the didanosine prescribing information.
NNRTI:
  Other NNRTIs
↑ or ↓ efavirenz and/or NNRTI Combining two NNRTIs has not been shown to be beneficial. ATRIPLA contains efavirenz and should not be coadministered with other NNRTIs.
Integrase strand transfer inhibitor:
  raltegravir
↓ raltegravir Efavirenz reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.
Hepatitis C antiviral agents
Protease inhibitor:
 boceprevir
↓ boceprevir Plasma trough concentrations of boceprevir were decreased when boceprevir was coadministered with efavirenz, which may result in loss of therapeutic effect. The combination should be avoided.
Protease inhibitor:
  simeprevir
↓ simeprevir
↔ efavirenz
Concomitant administration of simeprevir with efavirenz is not recommended because it may result in loss of therapeutic effect of simeprevir.
NS5A inhibitor/NS5B polymerase inhibitor :
  ledipasvir/sofosbuvir
↑ tenofovir Patients receiving ATRIPLA and HARVONI ® (ledipasvir/sofosbuvir) concomitantly should be monitored for adverse reactions associated with tenofovir DF.
Other agents
Anticoagulant:
  warfarin
↑ or ↓ warfarin Plasma concentrations and effects potentially increased or decreased by efavirenz.
Anticonvulsants:
  carbamazepine
↓ carbamazepine
↓ efavirenz
There are insufficient data to make a dose recommendation for ATRIPLA. Alternative anticonvulsant treatment should be used.
  phenytoin
  phenobarbital
↓ anticonvulsant
↓ efavirenz
Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted.
Antidepressants:
  bupropion
↓ buproprion The effect of efavirenz on bupropion exposure is thought to be due to the induction of bupropion metabolism. Increases in bupropion dosage should be guided by clinical response, but the maximum recommended dose of bupropion should not be exceeded.
  sertraline ↓ sertraline Increases in sertraline dose should be guided by clinical response.
Antifungals:
  itraconazole
↓ itraconazole
↓ hydroxy-itraconazole
Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered.
  ketoconazole ↓ ketoconazole Drug interaction trials with ATRIPLA and ketoconazole have not been conducted. Efavirenz has the potential to decrease plasma concentrations of ketoconazole.
  posaconazole ↓ posaconazole Avoid concomitant use unless the benefit outweighs the risks.
Anti-infective:
  clarithromycin
↓ clarithromycin
↑ 14-OH metabolite
Clinical significance unknown. In uninfected volunteers, 46% developed rash while receiving efavirenz and clarithromycin. No dose adjustment of ATRIPLA is recommended when given with clarithromycin. Alternatives to clarithromycin, such as azithromycin, should be considered. Other macrolide antibiotics, such as erythromycin, have not been studied in combination with ATRIPLA.
Antimycobacterial:
  rifabutin
↓ rifabutin Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week.
  rifampin ↓ efavirenz If ATRIPLA is coadministered with rifampin to patients weighing 50 kg or more, an additional 200 mg/day of efavirenz is recommended.
Antimalarials:
  artemether/lumefantrine
↓ artemether
↓ dihydroartemisinin
↓ lumefantrine
Artemether/lumefantrine should be used cautiously with ATRIPLA because decreased artemether, dihydroartemisinin (active metabolite of artemether), and/or lumefantrine concentrations may result in a decrease of antimalarial efficacy of artemether/lumefantrine.
Calcium channel blockers:
  diltiazem
↓ diltiazem
↓ desacetyl diltiazem
↓ N-monodes-methyl diltiazem
Diltiazem dose adjustments should be guided by clinical response (refer to the full prescribing information for diltiazem). No dose adjustment of ATRIPLA is necessary when administered with diltiazem.
  Others (e.g.,
  felodipine, nicardipine,
  nifedipine, verapamil)
↓ calcium channel blocker No data are available on the potential interactions of efavirenz with other calcium channel blockers that are substrates of CYP3A. The potential exists for reduction in plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response (refer to the full prescribing information for the calcium channel blocker).
HMG-CoA reductase inhibitors:
  atorvastatin
  pravastatin
  simvastatin
↓ atorvastatin
↓ pravastatin
↓ simvastatin
Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased with efavirenz. Consult the full prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose.
Hormonal contraceptives:
Oral:
  ethinyl
  estradiol/norgestimate
↓ active metabolites of norgestimate A reliable method of barrier contraception must be used in addition to hormonal contraceptives. Efavirenz had no effect on ethinyl estradiol concentrations, but progestin levels (norelgestromin and levonorgestrel) were markedly decreased. No effect of ethinyl estradiol/norgestimate on efavirenz plasma concentrations was observed.
Implant:
  etonogestrel
↓ etonogestrel A reliable method of barrier contraception must be used in addition to hormonal contraceptives. The interaction between etonogestrel and efavirenz has not been studied. Decreased exposure of etonogestrel may be expected. There have been postmarketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients.
Immunosuppressants:
  cyclosporine,
  tacrolimus, sirolimus,
  and others
  metabolized by
  CYP3A
↓ immuno-suppressant Decreased exposure of the immunosuppressant may be expected due to CYP3A induction by efavirenz. These immunosuppressants are not anticipated to affect exposure of efavirenz. Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with ATRIPLA.
Narcotic analgesic:
  methadone
↓ methadone Coadministration of efavirenz in HIV-1 infected individuals with a history of injection drug use resulted in decreased plasma levels of methadone and signs of opiate withdrawal. Methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms. Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7.1, 7.2, 7.3, 7.4)
Interacting Agents Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone Avoid simvastatin
Gemfibrozil, cyclosporine, danazol Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil Do not exceed 20 mg simvastatin daily
Diltiazem Do not exceed 40 mg simvastatin daily
Grapefruit juice Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.11, 7.3)


Table name:
Table 25: Clinically Important Drug Interactions with Aripiprazole:
Concomitant Drug Name or Drug Class Clinical Rationale Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)] . With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)] .
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin) The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)] . With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)] .
Antihypertensive Drugs Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.8)] .
Benzodiazepines (e.g., lorazepam) The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.8)] . Monitor sedation and blood pressure. Adjust dose accordingly.


Table name:
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitors (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.*
* Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol, systemic and inhaledamoxicillin
ampicillin, with or without sulbactamatenolol
azithromycincaffeine, dietary ingestion
cefaclorco-trimoxizole (trimethoprim and sulfamethoxazole)
diltiazemdirithromycin
enfluranefamotidine
felodipinefinasteride
hydrocortisoneisoflurane
isoniazidisradipine
influenza vaccineketoconazole
lomefloxacinmebendazole
medroxyprogesteronemethylprednisolone
metronidazolemetoprolol
nadololnifedipine
nizatidinenorfloxacin
ofloxacinomeprazole
prednisone, prednisoloneranitidine
rifabutinroxithromycin
sorbitol (purgative doses do not inhibit theophylline absorption)sucralfate
terfenadineterbutaline, systemic
tocainidetetracycline


Table name:
Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) VIAGRA 25 mg
Supine 7.4 (-0.9, 15.7)
Standing 6.0 (-0.8, 12.8)


Table name: Decreased Moxifloxacin Hydrochloride absorption. Take Moxifloxacin Hydrochloride Tablet at least 4 hours before or 8 hours after these products. (2.2, 7.1, 12.3)Anticoagulant effect enhanced. Monitor prothrombin time/INR, and bleeding. (6, 7.2, 12.3)Proarrhythmic effect may be enhanced. Avoid concomitant use. (5.3, 7.4)Carefully monitor blood glucose. (5.10, 7.3)
Interacting Drug Interaction
Multivalent cation-containing products including : antacids, sucralfate, multivitamins
Warfarin
Class IA and Class III antiarrhythmics:
Antidiabetic agents


Table name:
Table 8: Clinically Significant Drug Interactions with Clarithromycin
Drugs That Are Affected By Clarithromycin
Drug(s) with Pharmacokinetics Affected by Clarithromycin Recommendation Comments
Antiarrhythmics:


 
Disopyramide
Quinidine
Dofetilide
Amiodarone
Sotalol
Procainamide
Not Recommended Disopyramide, Quinidine: There have been postmarketing reports of torsades de pointes occurring with concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QTc prolongation during coadministration of clarithromycin with these drugs [see Warnings and Precautions (5.3)] .

Serum concentrations of these medications should also be monitored. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with disopyramide and quinidine.

There have been postmarketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide. Therefore, blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide.


Digoxin Use With Caution Digoxin: Digoxin is a substrate for P-glycoprotein (Pgp) and clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are co-administered, inhibition of Pgp by clarithromycin may lead to increased exposure of digoxin. Elevated digoxin serum concentrations in patients receiving clarithromycin and digoxin concomitantly have been reported in postmarketing surveillance. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Monitoring of serum digoxin concentrations should be considered, especially for patients with digoxin concentrations in the upper therapeutic range.


Oral Anticoagulants:


   
Warfarin Use With Caution Oral anticoagulants: Spontaneous reports in the postmarketing period suggest that concomitant administration of clarithromycin and oral anticoagulants may potentiate the effects of the oral anticoagulants. Prothrombin times should be carefully monitored while patients are receiving clarithromycin and oral anticoagulants simultaneously [see Warnings and Precautions (5.4)] .


Antiepileptics:


   
Carbamazepine Use With Caution Carbamazepine: Concomitant administration of single doses of clarithromycin and carbamazepine has been shown to result in increased plasma concentrations of carbamazepine. Blood level monitoring of carbamazepine may be considered. Increased serum concentrations of carbamazepine were observed in clinical trials with clarithromycin. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with carbamazepine.


Antifungals:


 
Itraconazole Use With Caution Itraconazole: Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when administered concomitantly (see also Itraconazole under “Drugs That Affect Clarithromycin” in the table below). Clarithromycin may increase the plasma concentrations of itraconazole. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions.


Fluconazole No Dose Adjustment


Fluconazole: [see Pharmacokinetics (12.3)]
Anti-Gout Agents:


 
Colchicine (in patients with renal or hepatic impairment)


Contraindicated Colchicine: Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. The dose of colchicine should be reduced when co-administered with clarithromycin in patients with normal renal and hepatic function [see Contraindications (4.4) and Warnings and Precautions (5.4)] .


Colchicine (in patients with normal renal and hepatic function) Use With Caution
Antipsychotics:


 
Pimozide Contraindicated Pimozide: [See Contraindications (4.2)]


Quetiapine Quetiapine: Quetiapine is a substrate for CYP3A4, which is inhibited by clarithromycin. Co-administration with clarithromycin could result in increased quetiapine exposure and possible quetiapine related toxicities. There have been postmarketing reports of somnolence, orthostatic hypotension, altered state of consciousness, neuroleptic malignant syndrome, and QT prolongation during concomitant administration. Refer to quetiapine prescribing information for recommendations on dose reduction if co-administered with CYP3A4 inhibitors such as clarithromycin.


Antispasmodics:


   
Tolterodine (patients deficient in CYP2D6 activity) Use With Caution Tolterodine: The primary route of metabolism for tolterodine is via CYP2D6. However, in a subset of the population devoid of CYP2D6, the identified pathway of metabolism is via CYP3A. In this population subset, inhibition of CYP3A results in significantly higher serum concentrations of tolterodine. Tolterodine 1 mg twice daily is recommended in patients deficient in CYP2D6 activity (poor metabolizers) when co-administered with clarithromycin.


Antivirals:


   
Atazanavir Use With Caution Atazanavir: Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction (see Atazanavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)] .


Saquinavir (in patients with decreased renal function)   Saquinavir: Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A and there is evidence of a bi-directional drug interaction (see Saquinavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)] .


Ritonavir
Etravirine
  Ritonavir, Etravirine: (see Ritonavir and Etravirine under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)] .


Maraviroc   Maraviroc: Clarithromycin may result in increases in maraviroc exposures by inhibition of CYP3A metabolism. See Selzentry ® prescribing information for dose recommendation when given with strong CYP3A inhibitors such as clarithromycin.


Boceprevir (in patients with normal renal function)

Didanosine
No Dose Adjustment Boceprevir: Both clarithromycin and boceprevir are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when co-administered. No dose adjustments are necessary for patients with normal renal function (see Victrelis ® prescribing information).


Zidovudine   Zidovudine: Simultaneous oral administration of clarithromycin immediate-release tablets and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine concentrations. Administration of clarithromycin and zidovudine should be separated by at least two hours [see Pharmacokinetics (12.3)] .

The impact of co-administration of clarithromycin extended-release tablets or granules and zidovudine has not been evaluated.


Calcium Channel Blockers:


   
Verapamil Use With Caution Verapamil: Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent verapamil, [see Warnings and Precautions (5.4)] .


Amlodipine
Diltiazem


  Amlodipine, Diltiazem: [See Warnings and Precautions (5.4)]
Nifedipine   Nifedipine: Nifedipine is a substrate for CYP3A. Clarithromycin and other macrolides are known to inhibit CYP3A. There is potential of CYP3A-mediated interaction between nifedipine and clarithromycin. Hypotension and peripheral edema were observed when clarithromycin was taken concomitantly with nifedipine [see Warnings and Precautions (5.4)] .


Ergot Alkaloids:


   
Ergotamine
Dihydroergotamine
Contraindicated Ergotamine, Dihydroergotamine: Postmarketing reports indicate that coadministration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system [see Contraindications (4.6)] .


Gastroprokinetic Agents:


   
Cisapride Contraindicated Cisapride: [See Contraindications (4.2)]


HMG-CoA Reductase Inhibitors:


   
Lovastatin
Simvastatin
Contraindicated Lovastatin, Simvastatin, Atorvastatin, Pravastatin, Fluvastatin: [See Contraindications (4.5) and Warnings and Precautions (5.4)]

Atorvastatin
Pravastatin


Use With Caution  
Fluvastatin

No Dose Adjustment


 
Hypoglycemic Agents:


   
Nateglinide
Pioglitazone
Repaglinide
Rosiglitazone


Use With Caution Nateglinide, Pioglitazone, Repaglinide, Rosiglitazone: [See Warnings and Precautions (5.4) and Adverse Reactions (6.2)]

Insulin   Insulin: [See Warnings and Precautions (5.4) and Adverse Reactions (6.2)]


Immunosuppressants:


   
Cyclosporine Use With Caution Cyclosporine: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with cyclosporine.


Tacrolimus   Tacrolimus: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with tacrolimus.


Phosphodiesterase inhibitors:


   
Sildenafil
Tadalafil
Vardenafil
Use With Caution Sildenafil, Tadalafil, Vardenafil: Each of these phosphodiesterase inhibitors is primarily metabolized by CYP3A, and CYP3A will be inhibited by concomitant administration of clarithromycin. Co-administration of clarithromycin with sildenafil, tadalafil, or vardenafil will result in increased exposure of these phosphodiesterase inhibitors. Co-administration of these phosphodiesterase inhibitors with clarithromycin is not recommended. Increased systemic exposure of these drugs may occur with clarithromycin; reduction of dosage for phosphodiesterase inhibitors should be considered (see their respective prescribing information).


Proton Pump Inhibitors:


   
Omeprazole No Dose Adjustment Omeprazole: The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when coadministered with clarithromycin as a result of increased omeprazole exposures [see Pharmacokinetics (12.3)] (see also Omeprazole under “Drugs That Affect Clarithromycin” in the table below).


Xanthine Derivatives:


   
Theophylline Use With Caution Theophylline: Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serum theophylline concentrations [see Pharmacokinetics (12.3)] . Monitoring of serum theophylline concentrations should be considered for patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range.


Triazolobenzodiazepines and Other Related Benzodiazepines:


   
Midazolam Use With Caution Midazolam: When oral midazolam is co-administered with clarithromycin, dose adjustments may be necessary and possible prolongation and intensity of effect should be anticipated [see Warnings and Precautions (5.4) and Pharmacokinetics (12.3)] .


Alprazolam
Triazolam
  Triazolam, Alprazolam: Caution and appropriate dose adjustments should be considered when triazolam or alprazolam is co-administered with clarithromycin. There have been postmarketing reports of drug interactions and central nervous system (CNS) effects (e.g., somnolence and confusion) with the concomitant use of clarithromycin and triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested.

In postmarketing experience, erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines.


Temazepam
Nitrazepam
Lorazepam
No Dose Adjustment Temazepam, Nitrazepam, Lorazepam: For benzodiazepines which are not metabolized by CYP3A (e.g., temazepam, nitrazepam, lorazepam), a clinically important interaction with clarithromycin is unlikely.


Cytochrome P450 Inducers:


   
Rifabutin Use With Caution Rifabutin: Concomitant administration of rifabutin and clarithromycin resulted in an increase in rifabutin, and decrease in clarithromycin serum levels together with an increased risk of uveitis (see Rifabutin under “Drugs That Affect Clarithromycin” in the table below).


Other Drugs Metabolized by CYP3A:


   
Alfentanil
Bromocriptine
Cilostazol
Methylprednisole
Vinblastine
Phenobarbital
St. John’s Wort


Use With Caution There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with alfentanil, methylprednisolone, cilostazol, bromocriptine, vinblastine, phenobarbital, and St. John’s Wort.
Other Drugs Metabolized by CYP450 Isoforms Other than CYP3A:


   
Hexobarbital
Phenytoin
Valproate
Use With Caution There have been postmarketing reports of interactions of clarithromycin with drugs not thought to be metabolized by CYP3A, including hexobarbital, phenytoin, and valproate.


Drugs that Affect Clarithromycin
Drug(s) that Affect the Pharmacokinetics of Clarithromycin Recommendation Comments
Antifungals:


   
Itraconazole

Use With Caution Itraconazole: Itraconazole may increase the plasma concentrations of clarithromycin. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions (see also Itraconazole under “Drugs That Are Affected By Clarithromycin” in the table above).


Antivirals:


   
Atazanavir Use With Caution Atazanavir: When clarithromycin is co-administered with atazanavir, the dose of clarithromycin should be decreased by 50% [see Clinical Pharmacology (12.3)] .

Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with atazanavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium complex. Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.


Ritonavir (in patients with decreased renal function)   Ritonavir: Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with ritonavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium [see Pharmacokinetics (12.3)] .

Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.


Saquinavir (in patients with decreased renal function)   Saquinavir: When saquinavir is co-administered with ritonavir, consideration should be given to the potential effects of ritonavir on clarithromycin (refer to ritonavir above) [see Pharmacokinetics (12.3)] .


Etravirine   Etravirine: Clarithromycin exposure was decreased by etravirine; however, concentrations of the active metabolite, 14-OH-clarithromycin, were increased. Because 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered; therefore alternatives to clarithromycin should be considered for the treatment of MAC.


Saquinavir (in patients with normal renal function) No Dose Adjustment  
Ritonavir (in patients with normal renal function)


   
Proton Pump Inhibitors:


   
Omeprazole Use With Caution Omeprazole: Clarithromycin concentrations in the gastric tissue and mucus were also increased by concomitant administration of omeprazole [see Pharmacokinetics (12.3)] .


Miscellaneous Cytochrome P450 Inducers:


 
Efavirenz
Nevirapine
Rifampicin
Rifabutin
Rifapentine
Use With Caution Inducers of CYP3A enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine will increase the metabolism of clarithromycin, thus decreasing plasma concentrations of clarithromycin, while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. Alternative antibacterial treatment should be considered when treating patients receiving inducers of CYP3A. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with rifabutin (see Rifabutin under “Drugs That Are Affected By Clarithromycin” in the table above).


Table name: Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol) In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. During concomitant use of diclofenac sodium topical gel and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of diclofenac sodium topical gel and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Drugs That Interfere with Hemostasis
Clinical Impact:
Intervention: Monitor patients with concomitant use of diclofenac sodium topical gel with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].
Intervention: Concomitant use of diclofenac sodium topical gel and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. Diclofenac sodium topical gel is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:
Intervention:
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of diclofenac sodium topical gel with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Digoxin
Clinical Impact: The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of diclofenac sodium topical gel and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of diclofenac sodium topical gel and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of diclofenac sodium topical gel and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of diclofenac sodium topical gel and cyclosporine may increase cyclosporine's nephrotoxicity.
Intervention: During concomitant use of diclofenac sodium topical gel and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention: The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of diclofenac sodium topical gel and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of diclofenac sodium topical gel and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and Gl toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.


Table name:
Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) VIAGRA 25 mg
Supine 7.4 (-0.9, 15.7)
Standing 6.0 (-0.8, 12.8)


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C Protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Digoxin concentrations increased greater than 50%
Digoxin Serum Concentration Increase Digoxin AUC Increase Recommendations
NA – Not available/reported
Amiodarone  70%  NA Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30 to 50% or by modifying the dosing frequency and continue monitoring.
Captopril  58%  39%
Clarithromycin  NA  70%
Dronedarone  NA  150%
Gentamicin  129 to 212%  NA
Erythromycin  100%  NA
Itraconazole  80%  NA
Lapatinib NA 180%
Nitrendipine  57%  15%
Propafenone  NA  60 to 270%
Quinidine  100%  NA
Ranolazine  50%  NA
Ritonavir  NA  86%
Telaprevir 50% 85%
Tetracycline  100%  NA
Verapamil  50 to 75%  NA
Digoxin concentrations increased less than 50%
Atorvastatin 22%  15% Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15 to 30% or by modifying the dosing frequency and continue monitoring.
Carvedilol 16%  14%
Conivaptan 33% 43%
Diltiazem 20%  NA
Indomethacin 40%  NA
Nefazodone 27%  15%
Nifedipine 45%  NA
Propantheline 24%  24%
Quinine NA  33%
Raberprazole 29% 19%
Saquinavir 27%  49%
Spironolactone 25%  NA
Telmisartan 20 to 49%  NA
Tricagrelor 31% 28%
Tolvaptan 30%  NA
Trimethoprim 22 to 28%  NA
Digoxin concentrations increased, but magnitude is unclear
Alprazolam, azithromycin, cyclosporine, diclofenac, diphenoxylate, epoprostenol, esomeprazole, ibuprofen, ketoconazole, lansoprazole, metformin, omeprazole Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin concentrations decreased
Acarbose, activated charcoal, albuterol, antacids, certain cancer chemotherapy or radiation therapy, cholestyramine, colestipol, extenatide, kaolin-pectin, meals high in bran, metoclopramide, miglitol, neomycin, penicillamine, phenytoin, rifampin, St. John's Wort, sucralfate, sulfasalazine Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20 to 40% as necessary.


Table name:
DRUGS EFFECT
Aspirin w/anti-inflammatory agents Increased
ulcerogenic effects.
Butalbital w/coumarin anticoagulants Decreased effect of
anticoagulant
because of
increased
metabolism
resulting from
enzyme induction.
Butalbital w/tricyclic antidepressants Decreased blood
levels of the
antidepressant.


Table name:
Interacting Drug
Interaction
Multivalent cation-containing products including antacids,
metal cations or didanosine
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin
Effect may be enhanced. Monitor prothrombin
time, INR, watch for bleeding (7.2)
Antidiabetic agents
Carefully monitor blood glucose (5.12, 7.3)


Table name:
CONCOMITANT DRUGCLINICAL EFFECT(S)
Amphetamines, cocaine, other sympathomimetic agentsAdditive hypertension, tachycardia, possibly cardiotoxicity
Atropine, scopolamine, antihistamines, other anticholinergic agentsAdditive or super-additive tachycardia, drowsiness
Amitriptyline, amoxapine, desipramine, other tricyclic antidepressantsAdditive tachycardia, hypertension, drowsiness
Barbiturates, benzodiazepines, ethanol, lithium, opioids, buspirone, antihistamines, muscle relaxants, other CNS depressantsAdditive drowsiness and CNS depression
DisulfiramA reversible hypomanic reaction was reported in a 28 y/o man who smoked marijuana; confirmed by dechallenge and rechallenge
FluoxetineA 21 y/o female with depression and bulimia receiving 20 mg/day fluoxetine X 4 wks became hypomanic after smoking marijuana; symptoms resolved after 4 days
Antipyrine, barbituratesDecreased clearance of these agents, presumably via competitive inhibition of metabolism
TheophyllineIncreased theophylline metabolism reported with smoking of marijuana; effect similar to that following smoking tobacco
OpioidsCross-tolerance and mutual potentiation
NaltrexoneOral THC effects were enhanced by opioid receptor blockade.
AlcoholIncrease in the positive subjective mood effects of smoked marijuana


Table name:
Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s) Recommendation Comments
Tizanidine Contraindicated Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)].
Theophylline Avoid Use (Plasma Exposure Likely to be Increased and Prolonged) Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate[see Warnings and Precautions (5.6).]
Drugs Known to Prolong QT Interval Avoid Use Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.10) and Use in Specific Populations (8.5)].
Oral antidiabetic drugs Use with caution Glucose-lowering effect potentiated Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs. [see Adverse Reactions (6.1).]
Phenytoin Use with caution Altered serum levels of phenytoin (increased and decreased) To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after coadministration of ciprofloxacin with phenytoin.
Cyclosporine Use with caution (transient elevations in serum creatinine) Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs Use with caution (Increase in anticoagulant effect) The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole Use with caution Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after coadministration with ciprofloxacin [see Warnings and Precautions (5.15)].
Clozapine Use with caution Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs Use with caution Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil Use with caution 2-fold increase in exposure Monitor for sildenafil toxicity (see Pharmacokinetics -(12.3)-].
Duloxetine Avoid Use 5-fold increase in duloxetine exposure If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products) Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2)]. Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels) Potentiation of ciprofloxacin toxicity may occur.


Table name:
Table 5 Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class: Drug Name Effect on Concentration of Boceprevir or Concomitant Drug Recommendations
Antiarrhythmics: amiodarone, bepridil, propafenone, quinidine

↑ antiarrhythmics

Coadministration with VICTRELIS has the potential to produce serious and/or life-threatening adverse events and has not been studied. Caution is warranted and therapeutic concentration monitoring of these drugs is recommended if they are used concomitantly with VICTRELIS.

digoxin ↑ digoxin Digoxin concentrations increased when administered with VICTRELIS [see Clinical Pharmacology (12.3)]. Measure serum digoxin concentrations before initiating VICTRELIS. Continue monitoring digoxin concentrations; consult the digoxin prescribing information for information on titrating the digoxin dose.
Anticoagulant: warfarin ↑ or ↓ warfarin Concentrations of warfarin may be altered when co-administered with VICTRELIS. Monitor INR closely.
Antidepressants: trazodone, desipramine ↑ trazodone
↑ desipramine
Plasma concentrations of trazodone and desipramine may increase when administered with VICTRELIS, resulting in adverse events such as dizziness, hypotension and syncope. Use with caution and consider a lower dose of trazodone or desipramine.
 
escitalopram ↓escitalopram Exposure of escitalopram was slightly decreased when coadministered with VICTRELIS. Selective serotonin reuptake inhibitors such as escitalopram have a wide therapeutic index, but doses may need to be adjusted when combined with VICTRELIS.
Antifungals: ketoconazoleThese combinations have been studied; see Clinical Pharmacology (12.3) for magnitude of interaction., itraconazole, posaconazole, voriconazole ↑ boceprevir

↑ itraconazole
↑ ketoconazole
↑ posaconazole
↑ voriconazole
Plasma concentrations of ketoconazole, itraconazole, voriconazole or posaconazole may be increased with VICTRELIS. When coadministration is required, doses of ketoconazole and itraconazole should not exceed 200 mg/day.
Anti-gout: colchicine ↑ colchicine Significant increases in colchicine levels are expected; fatal colchicine toxicity has been reported with other strong CYP3A4 inhibitors.

Patients with renal or hepatic impairment should not be given colchicine with VICTRELIS.

Treatment of gout flares (during treatment with VICTRELIS): 0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days.

Prophylaxis of gout flares (during treatment with VICTRELIS): If the original regimen was 0.6 mg twice a day, reduce dose to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, reduce the dose to 0.3 mg once every other day.

Treatment of familial Mediterranean fever (FMF) (during treatment with VICTRELIS): Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Anti-infective: clarithromycin ↑ clarithromycin Concentrations of clarithromycin may be increased with VICTRELIS; however, no dosage adjustment is necessary for patients with normal renal function.
Antimycobacterial:
rifabutin
↓ boceprevir
↑ rifabutin
Increases in rifabutin exposure are anticipated, while exposure of boceprevir may be decreased. Doses have not been established for the 2 drugs when used in combination. Concomitant use is not recommended.
Calcium Channel Blockers such as: amlodipine, diltiazem, felodipine, nifedipine, nicardipine, nisoldipine, verapamil ↑ calcium channel blockers Plasma concentrations of calcium channel blockers may increase when administered with VICTRELIS. Caution is warranted and clinical monitoring is recommended.
Corticosteroid, systemic: dexamethasone ↓ boceprevir Coadministration of VICTRELIS with CYP3A4/5 inducers may decrease plasma concentrations of boceprevir, which may result in loss of therapeutic effect. Therefore, this combination should be avoided if possible and used with caution if necessary.
prednisone ↑ prednisone Concentrations of prednisone and its active metabolite, prednisolone, increased when administered with VICTRELIS [see Clinical Pharmacology (12.3)]. No dose adjustment of prednisone is necessary when co-administered with VICTRELIS. Patients receiving prednisone and VICTRELIS should be monitored appropriately.
Corticosteroid, inhaled: budesonide, fluticasone ↑ budesonide
↑ fluticasone
Concomitant use of inhaled budesonide or fluticasone with VICTRELIS may result in increased plasma concentrations of budesonide or fluticasone, resulting in significantly reduced serum cortisol concentrations. Avoid coadministration if possible, particularly for extended durations.
Endothelin Receptor Antagonist: bosentan ↑ bosentan Concentrations of bosentan may be increased when coadministered with VICTRELIS. Use with caution and monitor closely.
HIV Integrase Inhibitor:
raltegravir
↔ raltegravir No dose adjustment required for VICTRELIS or raltegravir.
HIV Non-Nucleoside Reverse Transcriptase Inhibitors: efavirenz ↓ boceprevir Plasma trough concentrations of boceprevir were decreased when VICTRELIS was coadministered with efavirenz, which may result in loss of therapeutic effect. Avoid combination.

etravirine ↓ etravirine Concentrations of etravirine decreased when coadministered with VICTRELIS. The clinical significance of the reductions in etravirine pharmacokinetic parameters has not been directly assessed.
rilpivirine ↑ rilpivirine Concomitant administration of rilpivirine with VICTRELIS increased the exposure to rilpivirine. No dose adjustment of VICTRELIS or rilpivirine is recommended.
HIV Protease Inhibitors: atazanavir/ritonavir ↓ atazanavir
↓ ritonavir
Concomitant administration of boceprevir and atazanavir/ritonavir resulted in reduced steady-state exposures to atazanavir and ritonavir. Coadministration of atazanavir/ritonavir and boceprevir is not recommended.

darunavir/ritonavir ↓ darunavir
↓ ritonavir
↓ boceprevir
Concomitant administration of boceprevir and darunavir/ritonavir resulted in reduced steady-state exposures to boceprevir, darunavir and ritonavir. Coadministration of darunavir/ritonavir and boceprevir is not recommended.

lopinavir/ritonavir ↓ lopinavir
↓ ritonavir
↓ boceprevir
Concomitant administration of boceprevir and lopinavir/ritonavir resulted in reduced steady-state exposures to boceprevir, lopinavir and ritonavir. Coadministration of lopinavir/ritonavir and boceprevir is not recommended.

ritonavir ↓ boceprevir When boceprevir is administered with ritonavir alone, boceprevir concentrations are decreased.
HMG-CoA Reductase Inhibitors: For contraindicated HMG-CoA reductase inhibitors, [see Contraindications (4)].
atorvastatin ↑ atorvastatin Exposure to atorvastatin was increased when administered with VICTRELIS. Use the lowest effective dose of atorvastatin, but do not exceed a daily dose of 40 mg when coadministered with VICTRELIS.
 
pravastatin ↑ pravastatin Concomitant administration of pravastatin with VICTRELIS increased exposure to pravastatin. Treatment with pravastatin can be initiated at the recommended dose when coadministered with VICTRELIS. Close clinical monitoring is warranted.
Immunosuppressants: cyclosporine ↑cyclosporine
Dose adjustments of cyclosporine should be anticipated when administered with VICTRELIS and should be guided by close monitoring of cyclosporine blood concentrations, and frequent assessments of renal function and cyclosporine-related side effects.
 
tacrolimus ↑tacrolimus
Concomitant administration of VICTRELIS with tacrolimus requires significant dose reduction and prolongation of the dosing interval for tacrolimus, with close monitoring of tacrolimus blood concentrations and frequent assessments of renal function and tacrolimus-related side effects.
 
sirolimus ↑sirolimus
Concomitant administration of VICTRELIS with sirolimus requires significant dose reduction and prolongation of the dosing interval for sirolimus, with close monitoring of sirolimus blood concentrations and frequent assessments of renal function and sirolimus-related side effects.
Inhaled beta-agonist: salmeterol ↑ salmeterol Concurrent use of inhaled salmeterol and VICTRELIS is not recommended due to the risk of cardiovascular events associated with salmeterol.
Narcotic Analgesic/Opioid Dependence: methadone R-methadone Plasma concentrations of R-methadone decreased when coadministered with VICTRELIS [see Clinical Pharmacology (12.3)]. The observed changes are not considered clinically relevant. No dose adjustment of methadone or VICTRELIS is recommended. Individual patients may require additional titration of their methadone dosage when VICTRELIS is started or stopped to ensure clinical effect of methadone.

buprenorphine/naloxone ↑ buprenorphine/naloxone Plasma concentrations of buprenorphine and naloxone increased when coadministered with VICTRELIS [see Clinical Pharmacology (12.3)]. The observed changes are not considered clinically relevant. No dose adjustment of buprenorphine/naloxone or VICTRELIS is recommended.
Oral hormonal contraceptives: For contraindicated oral contraceptives, [see Contraindications (4)].

drospirenone/ethinyl estradiol ↑ drospirenone
↓ ethinyl estradiol
Concentrations of drospirenone increased in the presence of boceprevir. Thus, the use of drospirenone-containing products is contraindicated during treatment with VICTRELIS due to potential for hyperkalemia [see Contraindications (4)].

norethindrone/ethinyl estradiol ↓ ethinyl estradiol
↔ norethindrone
Concentrations of ethinyl estradiol decreased in the presence of boceprevir. Norethindrone Cmax decreased 17% in the presence of boceprevir [see Clinical Pharmacology (12.3)]. Coadministration of VICTRELIS with a combined oral contraceptive containing ethinyl estradiol and at least 1 mg of norethindrone is not likely to alter the effectiveness of this combined oral contraceptive [see Use in Specific Populations (8.1)].

Patients using estrogens as hormone replacement therapy should be clinically monitored for signs of estrogen deficiency.
PDE5 inhibitors: For contraindicated PDE5 enzyme inhibitors, [see Contraindications (4)].
sildenafil, tadalafil, vardenafil ↑ sildenafil
↑ tadalafil
↑ vardenafil
Increases in PDE5 inhibitor concentrations are expected, and may result in an increase in adverse events, including hypotension, syncope, visual disturbances, and priapism.

Use of REVATIO® (sildenafil) or ADCIRCA® (tadalafil) for the treatment of pulmonary arterial hypertension (PAH) is contraindicated with VICTRELIS [see Contraindications (4)].

Use of PDE5 inhibitors for erectile dysfunction:
Use with caution in combination with VICTRELIS with increased monitoring for PDE5 inhibitor-associated adverse events. Do not exceed the following doses:

Sildenafil: 25 mg every 48 hours

Tadalafil: 10 mg every 72 hours

Vardenafil: 2.5 mg every 24 hours
Proton Pump Inhibitor: omeprazole ↔ omeprazole No dose adjustment of omeprazole or VICTRELIS is recommended.
Sedative/hypnotics: For contraindicated sedatives/hypnotics, [see Contraindications (4)].
alprazolam; IV midazolam ↑ midazolam
↑ alprazolam
Close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised during coadministration of VICTRELIS. A lower dose of IV midazolam or alprazolam should be considered.


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class:
Drug Name
Effect on Concentration of Lopinavir or Concomitant Drug Clinical Comments
HIV-1 Antiviral Agents
HIV-1 Protease Inhibitor:
fosamprenavir/ritonavir
↓ amprenavir
↓ lopinavir
An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor:
indinavir*
↑ indinavir Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily. KALETRA once daily has not been studied in combination with indinavir.
HIV-1 Protease Inhibitor:
nelfinavir*
↑ nelfinavir
↑ M8 metabolite of nelfinavir
↓ lopinavir
KALETRA once daily in combination with nelfinavir is not recommended [see Dosage and Administration (2)].
HIV-1 Protease Inhibitor:
ritonavir*
↑ lopinavir Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor:
saquinavir
↑ saquinavir The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily.
KALETRA once daily has not been studied in combination with saquinavir.
HIV-1 Protease Inhibitor:
tipranavir*
↓ lopinavir Co-administration with tipranavir (500 mg twice daily) and ritonavir (200 mg twice daily) is not recommended.
HIV CCR5 – Antagonist:
maraviroc*
↑ maraviroc When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for maraviroc.
Non-nucleoside Reverse Transcriptase Inhibitors:
efavirenz*,
nevirapine*
↓ lopinavir Increase the dose of KALETRA tablets to 500/125 mg when KALETRA tablet is co-administered with efavirenz or nevirapine. KALETRA once daily in combination with efavirenz or nevirapine is not recommended [see Dosage and Administration (2)].
Non-nucleoside Reverse Transcriptase Inhibitor:
delavirdine
↑ lopinavir Appropriate doses of the combination with respect to safety and efficacy have not been established.
Nucleoside Reverse Transcriptase Inhibitor:
didanosine
  KALETRA tablets can be administered simultaneously with didanosine without food.
For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food).
Nucleoside Reverse Transcriptase Inhibitor:
tenofovir disoproxil fumarate*
↑ tenofovir Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir.
Nucleoside Reverse Transcriptase Inhibitors:
abacavir
zidovudine
↓ abacavir
↓ zidovudine
The clinical significance of this potential interaction is unknown.
Other Agents
Antiarrhythmics e.g.
amiodarone,
bepridil,
lidocaine (systemic),
quinidine
↑ antiarrhythmics For contraindicated antiarrhythmics, [see Contraindications (4)].
Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA.
Anticancer Agents:
vincristine,
vinblastine,
dasatinib,
nilotinib,
venetoclax
↑ anticancer agents For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when KALETRA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor.

A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as KALETRA. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions.

Coadministration of venetoclax and KALETRA may increase the risk of tumor lysis syndrome. Refer to the venetoclax prescribing information for dosing instructions.
Anticoagulants:
warfarin,
rivaroxaban
↑↓ warfarin



↑ rivaroxaban
Concentrations of warfarin may be affected. Initial frequent monitoring of the INR during KALETRA and warfarin co-administration is recommended.

Avoid concomitant use of rivaroxaban and KALETRA. Co-administration of KALETRA and rivaroxaban may lead to increased risk of bleeding.
Anticonvulsants:
carbamazepine,
phenobarbital,
phenytoin
↓ lopinavir
↓ phenytoin
KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution.
KALETRA once daily in combination with carbamazepine, phenobarbital, or phenytoin is not recommended.
In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA.
Anticonvulsants:
lamotrigine,
valproate
↓ lamotrigine
↓ or ↔ valproate
A dose increase of lamotrigine or valproate may be needed when co-administered with KALETRA and therapeutic concentration monitoring for lamotrigine may be indicated; particularly during dosage adjustments.
Antidepressant:
bupropion
↓ bupropion
↓ active metabolite,
hydroxybupropion
Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion.
Antidepressant:
trazodone
↑ trazodone Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. A lower dose of trazodone should be considered.
Anti-infective:
clarithromycin
↑ clarithromycin For patients with renal impairment, adjust clarithromycin dose as follows: For patients on KALETRA with CLCR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients on KALETRA with CLCR < 30 mL/min the dose of clarithromycin should be decreased by 75%. No dose adjustment for patients with normal renal function is necessary.
Antifungals:
ketoconazole*,
itraconazole,
voriconazole
isavuconazonium sulfate*
↑ ketoconazole
↑ itraconazole
↓ voriconazole
↑ isavuconazonium
High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended.
The coadministration of voriconazole and KALETRA should be avoided unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Isavuconazonium and Kaletra should be coadministered with caution. Alternative antifungal therapies should be considered in these patients.
Anti-gout:
colchicine
↑ colchicine Concomitant administration with colchicine is contraindicated in patients with renal and/or hepatic impairment [see Contraindications (4)].

For patients with normal renal or hepatic function:

Treatment of gout flares-co-administration of colchicine in patients on KALETRA:
0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days.

Prophylaxis of gout flares-co-administration of colchicine in patients on KALETRA:
If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.
If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.

Treatment of familial Mediterranean fever (FMF)-co-administration of colchicine in patients on KALETRA:
Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Antimycobacterial:
bedaquiline
↑ bedaquiline For contraindicated antimycobacterials, [see Contraindications (4)].
Bedaquiline should only be used with KALETRA if the benefit of co-administration outweighs the risk.
Antimycobacterial:
rifabutin*
↑ rifabutin and rifabutin metabolite Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary.
Antiparasitic:
atovaquone
↓ atovaquone Clinical significance is unknown; however, increase in atovaquone doses may be needed.
Antipsychotics: quetiapine ↑ quetiapine Initiation of KALETRA in patients taking quetiapine:
Consider alternative antiretroviral therapy to avoid increases in quetiapine exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring.

Initiation of quetiapine in patients taking KALETRA:
Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.
Sedative/hypnotics:
parenterally administered midazolam
↑ midazolam For contraindicated sedative/hypnotics,[see Contraindications (4)].
If KALETRA is co-administered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.
Contraceptive:
ethinyl estradiol*
↓ ethinyl estradiol Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended.
Systemic/Inhaled/ Nasal/Ophthalmic Corticosteroids:
e.g.,
betamethasone
budesonide
ciclesonide
dexamethasone
fluticasone
methylprednisolone
mometasone
prednisone
triamcinolone
↓ lopinavir



↑ glucocorticoids
Coadministration with oral dexamethasone or other systemic corticosteroids that induce CYP3A may result in loss of therapeutic effect and development of resistance to lopinavir. Consider alternative corticosteroids.

Coadministration with corticosteroids whose exposures are significantly increased by strong CYP3A inhibitors can increase the risk for Cushing’s syndrome and adrenal suppression.

Alternative corticosteroids including beclomethasone and prednisolone (whose PK and/or PD are less affected by strong CYP3A inhibitors relative to other studied steroids) should be considered, particularly for long-term use.
Dihydropyridine Calcium Channel Blockers: e.g.
felodipine,
nifedipine,
nicardipine
↑ dihydropyridine calcium channel blockers Clinical monitoring of patients is recommended and a dose reduction of the dihydropyridine calcium channel blocker may be considered.
Disulfiram/metronidazole   KALETRA oral solution contains ethanol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).
Endothelin Receptor Antagonists:
bosentan
↑ bosentan Co-administration of bosentan in patients on KALETRA:
In patients who have been receiving KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Co-administration of KALETRA in patients on bosentan:
Discontinue use of bosentan at least 36 hours prior to initiation of KALETRA.
After at least 10 days following the initiation of KALETRA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Hepatitis C direct acting antivirals:
boceprevir*

simeprevir

ombitasvir/paritaprevir/
ritonavir and dasabuvir*
↓ lopinavir
↓ boceprevir
↓ ritonavir

↑ simeprevir

↑ ombitasvir
↑ paritaprevir
↑ ritonavir
↔ dasabuvir
For contraindicated hepatitis C direct acting antivirals, [see Contraindications (4)].
It is not recommended to co-administer KALETRA and boceprevir, simeprevir, or ombitasvir/paritaprevir/ritonavir and dasabuvir.
HMG-CoA Reductase Inhibitors:
atorvastatin
rosuvastatin
↑ atorvastatin
↑ rosuvastatin
For contraindicated HMG-CoA reductase inhibitors, [see Contraindications (4)].
Use atorvastatin with caution and at the lowest necessary dose. Titrate rosuvastatin dose carefully and use the lowest necessary dose; do not exceed rosuvastatin 10 mg/day.
Immunosuppressants: e.g.
cyclosporine,
tacrolimus,
sirolimus
↑ immunosuppressants Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA.
Long-acting beta-adrenoceptor Agonist:
salmeterol
↑ salmeterol Concurrent administration of salmeterol and KALETRA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Narcotic Analgesics:
methadone,*
fentanyl
↓ methadone
↑ fentanyl
Dosage of methadone may need to be increased when co-administered with KALETRA.

Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with KALETRA.
PDE5 inhibitors:
avanafil,
sildenafil,
tadalafil,
vardenafil
↑ avanafil
↑ sildenafil
↑ tadalafil
↑ vardenafil
For contraindicated PDE5 inhibitors, [see Contraindications (4)].
Do not use KALETRA with avanafil because a safe and effective avanafil dosage regimen has not been established.

Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection.

Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH):

Sildenafil (Revatio®) is contraindicated [see Contraindications (4)].
The following dose adjustments are recommended for use of tadalafil (Adcirca®) with KALETRA:
Co-administration of ADCIRCA in patients on KALETRA:
In patients receiving KALETRA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Co-administration of KALETRA in patients on ADCIRCA:
Avoid use of ADCIRCA during the initiation of KALETRA. Stop ADCIRCA at least 24 hours prior to starting KALETRA. After at least one week following the initiation of KALETRA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Use of PDE5 inhibitors for erectile dysfunction:

It is recommended not to exceed the following doses:
  • Sildenafil: 25 mg every 48 hours
  • Tadalafil: 10 mg every 72 hours
  • Vardenafil: 2.5 mg every 72 hours
Use with increased monitoring for adverse events.
* see Clinical Pharmacology (12.3) for magnitude of interaction.


Table name:
Classes of Drugs
5-lipoxygenase Inhibitor
Adrenergic Stimulants, Central
Alcohol Abuse Reduction
Preparations
Analgesics
Anesthetics, Inhalation
Antiandrogen
Antiarrhythmics†
Antibiotics†
Aminoglycosides (oral)
Cephalosporins, parenteral
Macrolides
Miscellaneous
Penicillins, intravenous,
high dose
Quinolones
(fluoroquinolones)
Sulfonamides, long acting
Tetracyclines
Anticoagulants
Anticonvulsants†
Antidepressants†
Antimalarial Agents
Antineoplastics†
Antiparasitic/Antimicrobials
Antiplatelet Drugs/Effects
Antithyroid Drugs†
Beta-Adrenergic Blockers
Cholelitholytic Agents
Diabetes Agents, Oral
Diuretics†
Fungal Medications,
Intravaginal, Systemic†
Gastric Acidity and Peptic
Ulcer Agents†
Gastrointestinal
Prokinetic Agents
Ulcerative Colitis Agents
Gout Treatment Agents
Hemorrheologic Agents
Hepatotoxic Drugs
Hyperglycemic Agents
Hypertensive Emergency
Agents
Hypnotics†
Hypolipidemics†
Bile Acid-Binding Resins†
Fibric Acid Derivatives
HMG-CoA Reductase
Inhibitors†
Leukotriene Receptor
Antagonist
Monoamine Oxidase
Inhibitors
Narcotics, prolonged
Nonsteroidal Anti-
Inflammatory Agents
Proton Pump Inhibitors
Psychostimulants
Pyrazolones
Salicylates
Selective Serotonin
Reuptake Inhibitors
Steroids, Adrenocortical†
Steroids, Anabolic (17-Alkyl
Testosterone Derivatives)
Thrombolytics
Thyroid Drugs
Tuberculosis Agents†
Uricosuric Agents
Vaccines
Vitamins†


Table name:
Interacting Agents Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone Avoid simvastatin
Gemfibrozil, cyclosporine, danazol Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil Do not exceed 20 mg simvastatin daily
Diltiazem Do not exceed 40 mg simvastatin daily
Grapefruit juice Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
  Concomitant Drug   Effect on Concentration of Lamotrigine or Concomitant Drug   Clinical Comment
 Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel  ↓ lamotrigine
↓ levonorgestrel
 Decreased lamotrigine concentrations approximately 50%. Decrease in levonorgestrel component by 19%.
 Carbamazepine and carbamazepine epoxide  ↓ lamotrigine
? carbamazepine epoxide
 Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels.
 Lopinavir/ritonavir  ↓ lamotrigine  Decreased lamotrigine concentration approximately 50%.
 Atazanavir/ritonavir  ↓ lamotrigine  Decreased lamotrigine AUC approximately 32%.
 Phenobarbital/primidone  ↓ lamotrigine  Decreased lamotrigine concentration approximately 40%.
 Phenytoin  ↓ lamotrigine  Decreased lamotrigine concentration approximately 40%.
 Rifampin  ↓ lamotrigine  Decreased lamotrigine AUC approximately 40%.
 Valproate  ↑ lamotrigine
? valproate
 Increased lamotrigine concentrations slightly more than 2 fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.


Table name:
 
Drug Interactions Associated with Increased
Risk of Myopathy/Rhabdomyolysis (2.3 5.1, 7, 12.3)
Interacting Agents  Prescribing Recommendations
Strong CYP3A inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, and nefazodone), Erythromycin  Contraindicated with lovastatin
Gemfibrozil, cyclosporine  Avoid with lovastatin
Danazol, diltiazem, dronedarone, verapamil  Do not exceed 20 mg lovastatin daily
Amiodarone  Do not exceed 40 mg lovastatin daily
Grapefruit juice  Avoid grapefruit juice


Table name:
Table 6 Clinically Important Drug Interactions
Concomitant Drug Name or Drug Class Clinical Rationale Clinical Recommendation
Tricyclic antidepressants Increase blood pressure and may counteract clonidine’s hypotensive effects Monitor blood pressure and adjust as needed
Antihypertensive drugs Potentiate clonidine’s hypotensive effects Monitor blood pressure and adjust as needed
CNS depressants Potentiate sedating effects Avoid use
Drugs that affect sinus node function or AV node conduction (e.g., digitalis, calcium channel blockers, beta blockers) Potentiate bradycardia and risk of AV block Avoid use


Table name:
Table 3 Clinically Significant Drug Interactions with Meloxicam
Drugs  that  Interfere  with  Hemostasis
Clinical  Impact :
Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.
Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention :
Monitor patients with concomitant use of meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see  Warnings  and  Precautions  ( 5 . 11)].
Aspirin
Clinical  Impact :
Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see  Warnings  and  Precautions  ( 5 . 2)].
Intervention :
Concomitant use of meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see  Warnings  and  Precautions  ( 5 . 11)].
Meloxicam is not a substitute for low dose aspirin for cardiovascular protection.
ACE  Inhibitors Angiotensin  Receptor  Blockers or  Beta - Blockers
Clinical  Impact :
NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).
In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, coadministration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention :
During concomitant use of meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.
During concomitant use of meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see  Warnings  and  Precautions  ( 5 . 6 )].
When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical  Impact :
Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam.
Intervention :
During concomitant use of meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see  Warnings  and  Precautions  ( 5 . 6)].
Lithium
Clinical  Impact :
NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [see  Clinical  Pharmacology  ( 12 . 3)].
Intervention :
During concomitant use of meloxicam and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical  Impact :
Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention :
During concomitant use of meloxicam and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical  Impact :
Concomitant use of meloxicam and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention :
During concomitant use of meloxicam and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs  and  Salicylates
Clinical  Impact :
Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see  Warnings  and  Precautions  ( 5 . 2)].
Intervention :
The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical  Impact :
Concomitant use of meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention :
During concomitant use of meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.
Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended.


Table name:
Table 1: Drugs that may have their plasma concentrations increased by itraconazole
Drug Class Contraindicated Not Recommended Use with Caution Comments
Under no circumstances is the drug to be coadministered with itraconazole , and up to two weeks after discontinuation of treatment with itraconazole . It is recommended that the use of the drug be avoided during and up to two weeks after discontinuation of treatment with itraconazole , unless the benefits outweigh the potentially increased risks of side effects. If coadministration cannot be avoided, clinical monitoring for signs or symptoms of increased or prolonged effects or side effects of the interacting drug is recommended, and its dosage be reduced or interrupted as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured. The label of the coadministered drug should be consulted for information on dose adjustment and adverse effects. Careful monitoring is recommended when the drug is coadministered with itraconazole . Upon coadministration , it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of the interacting drug, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured. The label of the coadministered drug should be consulted for information on dose adjustment and adverse effects.
Alpha Blockers tamsulosin
Analgesics methadone alfentanil,
buprenorphine IV and sublingual,
fentanyl,
oxycodone,
sufentanil
Methadone: The potential increase in plasma concentrations of methadone when coadministered with itraconazole may increase the risk of serious cardiovascular events including QTc prolongation and torsade de pointes.
Fentanyl: The potential increase in plasma concentrations of fentanyl when coadministered with itraconazole may increase the risk of potentially fatal respiratory depression.
Sufentanil : No human pharmacokinetic data of an interaction with itraconazole are available. In vitro data suggest that sufentanil is metabolized by CYP3A4 and so potentially increased sufentanil plasma concentrations would be expected when coadministered with itraconazole.
Antiarrhythmics disopyramide,
dofetilide,
dronedarone,
quinidine
digoxin Disopyramide , dofetilide , dronedarone , quinidine: The potential increase in plasma concentrations of these drugs when coadministered with itraconazole may increase the risk of serious cardiovascular events including QTc prolongation.
Antibacterials telithromycin, in subjects with severe renal impairment or severe hepatic impairment rifabutin telithromycin Telithromycin : The potential increase in plasma concentrations of telithromycin in subjects with severe renal impairment or severe hepatic impairment, when coadministered with itraconazole may increase the risk of serious cardiovascular events including QT prolongation and torsade de pointes. Rifabutin : See also under 'Drugs that may decrease itraconazole plasma concentrations'.
Anticoagulants and Antiplatelet Drugs ticagrelor apixaban, rivaroxaban coumarins,
cilostazol,
dabigatran
Ticagrelor : The potential increase in plasma concentrations of ticagrelor may increase the risk of bleeding. Coumarins : Itraconazole may enhance the anticoagulant effect of coumarin-like drugs, such as warfarin.
Anticonvulsants carbamazepine Carbamazepine: In vivo studies have demonstrated an increase in plasma carbamazepine concentrations in subjects concomitantly receiving ketoconazole. Although there are no data regarding the effect of itraconazole on carbamazepine metabolism, because of the similarities between ketoconazole and itraconazole, concomitant administration of itraconazole and carbamazepine may inhibit the metabolism of carbamazepine. See also under 'Drugs that may decrease itraconazole plasma concentrations'.
Antidiabetics repaglinide,
saxagliptin
Antihelmintics and Antiprotozoals praziquantel
Antimigraine Drugs ergot alkaloids, such as dihydroergotamine,
ergometrine (ergonovine),
ergotamine,
methylergometrine (methylergonovine)
eletriptan Ergot Alkaloids: The potential increase in plasma concentrations of ergot alkaloids when coadministered with itraconazole may increase the risk of ergotism, i.e., a risk for vasospasm potentially leading to cerebral ischemia and/or ischemia of the extremities.
Antineoplastics irinotecan axitnib,
dabrafenib,
dasatinib,
ibrutinib,
nilotinib,
sunitinib
bortezomib,
busulphan,
docetaxel,
erlotinib,
imatinib,
ixabepilone,
lapatinib,
ponatinib,
trimetrexate,
vinca alkaloids
Irinotecan: The potential increase in plasma concentrations of irinotecan when coadministered with itraconazole may increase the risk of potentially fatal adverse events.
Antipsychotics, Anxiolytics and Hypnotics lurasidone,
oral midazolam,
pimozide,
triazolam
alprazolam,
aripiprazole,
buspirone,
diazepam,
haloperidol,
midazolam IV,
perospirone,
quetiapine,
ramelteon,
risperidone
Midazolam, triazolam: Coadministration of itraconazole and oral midazolam, or triazolam may cause several-fold increases in plasma concentrations of these drugs. This may potentiate and prolong hypnotic and sedative effects, especially with repeated dosing or chronic administration of these agents.
Pimozide : The potential increase in plasma concentrations of pimozide when coadministered with itraconazole may increase the risk of serious cardiovascular events including QTc prolongation and torsade de pointes.
Antivirals simeprevir maraviroc,
indinavir,
ritonavir,
saquinavir
Indinavir , ritonavir: See also under 'Drugs that may increase itraconazole plasma concentrations'.
Beta Blockers nadolol
Calcium Channel Blockers felodipine,
nisoldipine
other dihydropyridines,
verapamil
Calcium channel blockers can have a negative inotropic effect which may be additive to those of itraconazole. The potential increase in plasma concentrations of calcium channel blockers when co-administered with itraconazole may increase the risk of congestive heart failure. Dihydropyridines : Concomitant administration of itraconazole may cause several-fold increases in plasma concentrations of dihydropyridines. Edema has been reported in patients concomitantly receiving itraconazole and dihydropyridine calcium channel blockers.
Cardiovascular Drugs, Miscellaneous ranolazine aliskiren,
sildenafil, for the treatment of pulmonary hypertension
bosentan,
riociguat
Ranolazine : The potential increase in plasma concentrations of ranolazine when coadministered with itraconazole may increase the risk of serious cardiovascular events including QTc prolongation.
Diuretics eplerenone Eplerenone : The potential increase in plasma concentrations of eplerenone when coadministered with itraconazole may increase the risk of hyperkalemia and hypotension.
Gastrointestinal Drugs cisapride aprepitant Cisapride : The potential increase in plasma concentrations of cisapride when coadministered with itraconazole may increase the risk of serious cardiovascular events including QTc prolongation.
Immunosuppressants everolimus,
temsirolimus
budesonide,
ciclesonide,
cyclosporine,
dexamethasone,
fluticasone,
methylprednisolone,
rapamycin (also known as sirolimus),
tacrolimus
Lipid Regulating Drugs lovastatin,
simvastatin
atorvastatin The potential increase in plasma concentrations of atorvastatin, lovastatin, and simvastatin when coadministered with itraconazole may increase the risk of skeletal muscle toxicity, including rhabdomyolysis.
Respiratory Drugs salmeterol
Urological Drugs fesoterodine, in subjects with moderate to severe renal impairment, or moderate to severe hepatic impairment, solifenacin, in subjects with severe renal impairment or moderate to severe hepatic impairment darifenacin,
vardenafil
fesoterodine,
oxybutynin,
sildenafil, for the treatment of erectile dysfunction,
solifenacin,
tadalafil,
tolterodine
Fesoterodine : The potential increase in plasma concentrations of the fesoterodine active metabolite may be greater in subjects with moderate to severe renal impairment, or moderate to severe hepatic impairment, which may lead to an increased risk of adverse reactions.
Solifenacin: The potential increase in plasma concentrations of solifenacin in subjects with severe renal impairment or moderate to severe hepatic impairment, when coadministered with itraconazole may increase the risk of serious cardiovascular events including QT prolongation.
Other colchicine, in subjects with renal or hepatic impairment colchicine,
conivaptan,
tolvaptan
cinacalcet Colchicine: The potential increase in plasma concentrations of colchicine when coadministered with itraconazole may increase the risk of potentially fatal adverse events.
Conivaptan and Tolvaptan : A safe and effective dose of either conivaptan or tolvaptan has not been established when coadministered with itraconazole.


Table name:
Table 3: Clinically Significant Drug Interactions with ADDYI
Alcohol
Clinical Implications The concomitant use of ADDYI with alcohol increased the risk of hypotension, syncope, and CNS depression compared to the use of ADDYI alone or alcohol alone [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.2)].
Preventing or Managing DI The concomitant use of ADDYI with alcohol is contraindicated.
Other CNS Depressants
Examples Diphenhydramine, opioids, hypnotics, benzodiazepines
Clinical Implications The concomitant use of ADDYI with CNS depressants may increase the risk of CNS depression (e.g., somnolence) compared to the use of ADDYI alone.
Preventing or Managing DI Discuss the concomitant use of other CNS depressants with the patient when prescribing ADDYI.
Moderate or Strong CYP3A4 Inhibitors
Examples of strong CYP3A4 inhibitors Ketoconazole, itraconazole, posaconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, boceprevir, telaprevir, telithromycin and conivaptan
Examples of moderate CYP3A4 inhibitors Amprenavir, atazanavir, ciprofloxacin, diltiazem, erythromycin, fluconazole, fosamprenavir, verapamil, and grapefruit juice
Clinical Implications The concomitant use of ADDYI with moderate or strong CYP3A4 inhibitors increases flibanserin exposure compared to the use of ADDYI alone. The risk of hypotension and syncope is increased with concomitant use of ADDYI and moderate or strong CYP3A4 inhibitors [see Warnings and Precautions (5.3), Adverse Reactions (6.1), and Clinical Pharmacology (12.3)].
Preventing or Managing DI The concomitant use of ADDYI with moderate or strong CYP3A4 inhibitors is contraindicated.
Weak CYP3A4 Inhibitors
Examples Oral contraceptives, cimetidine, fluoxetine, ginkgo, ranitidine
Clinical Implications The concomitant use of ADDYI with multiple weak CYP3A4 inhibitors may increase the risk of adverse reactions.
Preventing or Managing DI Discuss the use of multiple weak CYP3A4 inhibitors with the patient when prescribing ADDYI.
Strong CYP2C19 Inhibitors
Examples Proton pump inhibitors, selective serotonin reuptake inhibitors, benzodiazepines, antifungals
Clinical Implications The concomitant use of ADDYI with strong CYP2C19 inhibitors may increase flibanserin exposure which may increase the risk of hypotension, syncope, and CNS depression.
Preventing or Managing DI Discuss the use of a strong CYP2C19 inhibitor with the patient when prescribing ADDYI.
CYP3A4 Inducers
Examples Carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapetine, St. John's Wort
Clinical Implications The concomitant use of ADDYI with CYP3A4 inducers substantially decreases flibanserin exposure compared to the use of ADDYI alone.
Preventing or Managing DI The concomitant use of ADDYI with CYP3A4 inducers is not recommended.
Digoxin or Other P-glycoprotein Substrates
Examples Digoxin, sirolimus
Clinical Implications The concomitant use of ADDYI with digoxin, a drug that is transported by P-glycoprotein (P-gp), increases the digoxin concentration [see Clinical Pharmacology (12.3)].  This may lead to digoxin toxicity.
Preventing or Managing DI Increase monitoring of concentrations of drugs transported by P-gp that have a narrow therapeutic index (e.g., digoxin).  


Table name:
Drug Interactions Associated with Increased Risk of  Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice Avoid grapefruit juice


Table name:
Inhibitors of CYP3A4
Clinical Impact: The concomitant use of fentanyl transdermal system and CYP3A4 inhibitors can increase the plasma concentration of fentanyl, resulting in increased or prolonged opioid effects particularly when an inhibitor is added after a stable dose of fentanyl transdermal system is achieved [see Warnings and Precautions (5.5)].

After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the fentanyl transdermal system plasma concentration will decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to fentanyl.
Intervention: If concomitant use is necessary, consider dosage reduction of fentanyl transdermal system until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals.

If a CYP3A4 inhibitor is discontinued, consider increasing the fentanyl transdermal system dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
Examples Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir), grape fruit juice
CYP3A4 Inducers
Clinical Impact: The concomitant use of fentanyl transdermal system and CYP3A4 inducers can decrease the plasma concentration of fentanyl [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to fentanyl [see Warnings and Precautions (5.5)].

After stopping a CYP3A4 inducer, as the effects of the inducer decline, the fentanyl plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.
Intervention: If concomitant use is necessary, consider increasing the fentanyl transdermal system dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider fentanyl transdermal system dosage reduction and monitor for signs of respiratory depression.
Examples: Rifampin, carbamazepine, phenytoin
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.7)].
Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Warnings and Precautions 5.10].
Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue fentanyl transdermal system if serotonin syndrome is suspected.
Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome [see Warnings and Precautions (5.10)] or opioid toxicity (e.g., respiratory depression, coma).
Intervention: The use of fentanyl transdermal system is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples: phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact: May reduce the analgesic effect of fentanyl transdermal system and/or precipitate withdrawal symptoms.
Intervention: Avoid concomitant use.
Examples: butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact: Fentanyl transdermal system may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of fentanyl transdermal system and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when fentanyl transdermal system is used concomitantly with anticholinergic drugs.


Table name:
Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) VIAGRA 50 mg (95% CI)
Supine 9.08 (5.48, 12.68)
Standing

11.62 (7.34, 15.90)



Table name:
Drug/Drug Class (Mechanism of Interaction by the Drug) Voriconazole Plasma Exposure
(Cmax and AUC
τ after 200 mg q12h)
Recommendations for Voriconazole Dosage Adjustment/Comments
Rifampin* and Rifabutin* (CYP450 Induction) Significantly Reduced Contraindicated
Efavirenz (400 mg q24h)** (CYP450 Induction)

Efavirenz (300 mg q24h)** (CYP450 Induction)
Significantly Reduced



Slight Decrease in AUCτ
Contraindicated



When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High dose Ritonavir (400 mg q12h)** (CYP450 Induction)
Low dose Ritonavir (100 mg q12h)** (CYP450 Induction)
Significantly Reduced


Reduced
Contraindicated


Coadministration of voriconazole and low dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Carbamazepine (CYP450 Induction) Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction Contraindicated
Long Acting Barbiturates (CYP450 Induction) Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction Contraindicated
Phenytoin* (CYP450 Induction) Significantly Reduced Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg)
St. John’s Wort (CYP450 inducer; P-gp inducer) Significantly Reduced Contraindicated
Oral Contraceptives** containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition) Increased Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole** (CYP2C9, CYP2C19 and CYP3A4 Inhibition) Significantly Increased Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole
Other HIV Protease Inhibitors (CYP3A4 Inhibition) In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure
In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)
No dosage adjustment in the voriconazole dosage needed when coadministered with
indinavir

Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIs*** (CYP3A4 Inhibition or CYP450 Induction) In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure)
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure)
Frequent monitoring for adverse events and toxicity related to voriconazole


Careful assessment of voriconazole effectiveness


Table name:
Table 4. Drugs That May Alter Hepatic Metabolism of T4 (Hypothyroidism)
Potential impact: Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased SYNTHROID requirements.
Drug or Drug Class Effect
Phenobarbital
Rifampin
Phenobarbital has been shown to reduce the response to thyroxine. Phenobarbital increases L-thyroxine metabolism by inducing uridine 5’-diphospho-glucuronosyltransferase (UGT) and leads to a lower T4 serum levels. Changes in thyroid status may occur if barbiturates are added or withdrawn from patients being treated for hypothyroidism. Rifampin has been shown to accelerate the metabolism of levothyroxine.


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function.
Drugs that may alter T4 and T3 serum transport - but FT4 concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin/Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens/Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non-Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4 . Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ³ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias
and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123 I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Concomitant Drug   Effect onConcentration ofLamotrigine orConcomitant Drug Clinical Comment  
Estrogen-containing oralcontraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine   
↓ levonorgestrel
Decreased lamotrigine concentrationsapproximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepineand carbamazepine epoxide   ↓ lamotrigine  
? carbamazepine epoxide
Addition of carbamazepine decreases lamotrigine concentration approximately 40%.May increase carbamazepine epoxide levels.
Lopinavir/ritonavir ↓ lamotrigine Decreased lamotrigine concentrationapproximately 50%.
Atazanavir/ritonavir ↓ lamotrigine Decreased lamotrigine AUCapproximately 32%.
     
Phenobarbital/primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine  
? valproate  
Increased lamotrigine concentrations slightly more than 2-fold.There are conflicting study resultsregarding effect of lamotrigine onvalproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change invalproate concentrations in controlled clinical trials in patients with epilepsy.


Table name:
Oral hypoglycemics Tofacitinib Cyclophosphamide
Coumarin-type anticoagulants  Triazolam Fentanyl
Phenytoin Oral contraceptives Halofantrine
Cyclosporine Pimozide HMG-CoA reductase inhibitors
Rifampin Quinidine Losartan
Theophylline Hydrochlorothiazide Methadone
Terfenadine Alfentanil Non-steroidal anti-inflammatory drugs
Cisapride Amitriptyline, nortriptyline Prednisone
Astemizole Amphotericin B Saquinavir
Rifabutin Azithromycin Sirolimus
Voriconazole Carbamazepine Vinca alkaloids
Tacrolimus Calcium channel blockers Vitamin A
Short-acting benzodiazepines Celecoxib Zidovudine


Table name:
Classes of Drugs
5-lipoxygenase Inhibitor
Adrenergic Stimulants, Central
Alcohol Abuse Reduction
  Preparations
Analgesics
Anesthetics, Inhalation
Antiandrogen
Antiarrhythmics†
Antibiotics†
  Aminoglycosides (oral)
  Cephalosporins, parenteral
  Macrolides
  Miscellaneous
  Penicillins, intravenous,
    high dose
  Quinolones
    (fluoroquinolones)
  Sulfonamides, long acting
  Tetracyclines
Anticoagulants
Anticonvulsants†
Antidepressants†
Antimalarial Agents
Antineoplastics†
Antiparasitic/Antimicrobials
Antiplatelet Drugs/Effects
Antithyroid Drugs†
Beta-Adrenergic Blockers
Cholelitholytic Agents
Diabetes Agents, Oral
Diuretics†
Fungal Medications,
  Intravaginal, Systemic†
Gastric Acidity and Peptic
  Ulcer Agents†
Gastrointestinal
  Prokinetic Agents
  Ulcerative Colitis Agents
Gout Treatment Agents
Hemorrheologic Agents
Hepatotoxic Drugs
Hyperglycemic Agents
Hypertensive Emergency
  Agents
Hypnotics†
Hypolipidemics†
  Bile Acid-Binding Resins†
  Fibric Acid Derivatives
  HMG-CoA Reductase
    Inhibitors†
Leukotriene Receptor
  Antagonist
Monoamine Oxidase
  Inhibitors
Narcotics, prolonged
Nonsteroidal Anti-
  Inflammatory Agents
Proton Pump Inhibitors
Psychostimulants
Pyrazolones
Salicylates
Selective Serotonin
  Reuptake Inhibitors
Steroids, Adrenocortical†
Steroids, Anabolic (17-Alkyl
  Testosterone Derivatives)
Thrombolytics
Thyroid Drugs
Tuberculosis Agents†
Uricosuric Agents
Vaccines
Vitamins†


Table name:
Concomitant Drug
Effect on
Concentration of
Lamotrigine or
Concomitant Drug
Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel
↓ lamotrigine
 
 
↓ levonorgestrel
Decreased lamotrigine concentrations approximately 50%.
Decrease in levonorgestrel component by 19%.
Carbamazepine
and carbamazepine epoxide
↓ lamotrigine
 
 
 
? carbamazepine epoxide
Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
 
May increase carbamazepine epoxide levels.
Lopinavir/ritonavir
↓ lamotrigine
Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir
↓ lamotrigine
Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone
↓ lamotrigine
Decreased lamotrigine concentration approximately 40%.
Phenytoin
↓ lamotrigine
Decreased lamotrigine concentration approximately 40%.
Rifampin
↓ lamotrigine
Decreased lamotrigine AUC approximately 40%.
Valproate
↑ lamotrigine
 
 
 
? valproate
Increased lamotrigine concentrations slightly more than 2-fold.
 
There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.


Table name:
Table 2: Rifabutin Interaction Studies
↑ indicates increase; ↓ indicates decrease; ↔ indicates no significant change
QD-once daily; BID-twice daily; TID – thrice daily
ND -No Data
AUC -Area under the Concentration vs. Time Curve; C max -Maximum serum concentration
a compared to rifabutin 300 mg QD alone
b compared to historical control (fosamprenavir/ritonavir 700/100 mg BID)
c also taking zidovudine 500 mg QD
d compared to rifabutin 150 mg QD alone
e compared to rifabutin 300 mg QD alone
f data from a case report
g compared to voriconazole 200 mg BID alone
Coadministered
drug
Dosing regimen
of coadministered
drug
Dosing
regimen of
rifabutin
Study
population
(n)
Effect on
rifabutin
Effect on
coadministered
drug
Recommendation
ANTIVIRALS
Amprenavir 1200 mg BID x
10 days
300 mg QD
x 10 days
Healthy male
subjects (6)
↑ AUC by 193%,
↑ C max by 119%
Reduce rifabutin dose by at least
50%. Monitor closely for adverse
reactions.
Delavirdine 400 mg TID 300 mg QD HIV-infected
patients (7)
↑ AUC by 230%,
↑ C max by 128%
↓ AUC by 80%,
↓ Cmax by 75%,
↓ C min by 17%
CONTRAINDICATED
Didanosine 167 or 250 mg BID
x 12 days
300 or 600
mg QD x 1
HIV-infected
patients (11)
Fosamprenavir/
ritonavir
700 mg BID plus
ritonavir 100 mg
BID x 2 weeks
150 mg
every other
day x 2 weeks
Healthy
subjects (15)
↔ AUC a
↓ C max by 15%
↑ AUC by 35% b,
↑ C max by 36%,
↑ C min by 36%
Reduce rifabutin dose by at least
75% (to a maximum 150 mg every
other day or three times per week)
when given with fosamprenavir/
ritonavir combination.
Indinavir 800 mg TID
x 10 days
300 mg QD
x 10 days
Healthy
subjects (10)
↑ AUC by 173%,
↑ C max by 134%
↓ AUC by 34%,
↓ C max by 25%,
↓ C min by 39%
Reduce rifabutin dose by 50%, and
increase indinavir dose from 800 mg
to 1000 mg TID.
Lopinavir/
ritonavir
400/100 mg BID
x 20 days
150 mg QD
x 10 days
Healthy
subjects (14)
↑ AUC by 203% c
↓ C max by 112%
Reduce rifabutin dose by at least
75% (to a maximum 150 mg every
other day or three times per week)
when given with lopinavir/ritonavir
combination. Monitor closely for
adverse reactions. Reduce rifabutin
dosage further, as needed.
Saquinavir/
ritonavir
1000/100 mg BID
x 14 or 22 days
150 mg every
3 days X 21 to
22 days
Healthy
subjects
↑ AUC by 53% d
↑ C max by 88% (n=11)
↓ AUC by 13%,
↓ C max by 15%,
(n=19)
Reduce rifabutin dose by at least
75% (to a maximum 150 mg every
other day or three times per week)
when given with saquinavir/ritonavir
combination. Monitor closely for
adverse reactions.
Ritonavir 500 mg BID
x 10 days
150 mg QD
x 16 days
Healthy
subjects (5)
↑ AUC by 300%,
↑ C max by 150%
ND Reduce rifabutin dose by at least
75% (to a maximum 150 mg every
other day or three times per week)
when given with lopinavir/ritonavir
combination. Monitor closely for
adverse reactions. Reduce rifabutin
dosage further, as needed.
Tipranavir/
ritonavir
500/200 BID
X 15 doses
150 mg
single dose
Healthy
subjects (20)
↑ AUC by 190%,
↑ C max by 70%
Reduce rifabutin dose by at least
75% (to a maximum 150 mg every
other day or three times per week)
when given with tipranavir/ritonavir
combination. Monitor closely for
adverse reactions. Reduce rifabutin
dosage further, as needed.
Nelfinavir 1250 mg BID
x 7 to 8 days
150 mg QD
x 8 days
HIV-infected
patients (11)
↑ AUC by 83%, e
↑ C max by 19%
Reduce rifabutin dose by 50%
(to 150 mg QD) and increase the
nelfinavir dose to 1250 mg BID
Zidovudine 100 or 200 mg
q4h
300 or 450
mg QD
HIV-infected
patients (16)
↓ AUC by 32%,
↓ C max by 48%
Because zidovudine levels remained
within the therapeutic range during
coadministration of rifabutin, dosage
adjustments are not necessary.
ANTIFUNGALS
Fluconazole 200 mg QD
x 2 weeks
300 mg QD
x 2 weeks
HIV-infected
patients (12)
↑ AUC by 82%,
↑C max by 88%
Monitor for rifabutin associated
adverse events. Reduce rifabutin
dose or suspend rifabutin use if
toxicity is suspected.
Posaconazole 200 mg QD
x 10 days
300 mg QD
x 17 days
Healthy
subjects (8)
↑ AUC by 72%,
↑ C max by 31%
↓ AUC by 49%,
↓ C max by 43%
If co-administration of these two
drugs cannot be avoided, patients
should be monitored for adverse
events associated with rifabutin
administration, and lack of
posaconazole efficacy.
Itraconazole 200 mg QD 300 mg QD HIV-Infected
patients (6)
f ↓ AUC by 70%,
↓ C max by 75%
If co-administration of these two
drugs cannot be avoided, patients
should be monitored for adverse
events associated with rifabutin
administration, and lack of
itraconazole efficacy. In a separate
study, one case of uveitis was
associated with increased serum
rifabutin levels following
coadministration of rifabutin
(300 mg QD) with itraconazole
(600 to 900 mg QD).
Voriconazole 400 mg BID
x 7 days
(maintenance
dose)
300 mg QD
x 7 days
Healthy male
subjects (12)
↑ AUC by 331%,
↑ C max by 195%
↑ AUC by ~100%,
↑ C max by ~100% g
CONTRAINDICATED
ANTI-PCP (Pneumocystis carinii pneumonia)
Dapsone 50 mg QD 300 mg QD HIV-infected
patients (16)
ND ↓ AUC by 27 to 40%
Sulfamethoxazole
-Trimethoprim
800/160 mg 300 mg QD HIV-infected
patients (12)
↓ AUC by 15 to 20%
ANTI-MAC (Mycobacterium avium intracellulare complex)
Azithromycin 500 mg QD
x 1 day, then
250 mg QD
x 9 days
300 mg QD Healthy
subjects (6)
Clarithromycin 500 mg BID 300 mg QD HIV-infected
patients (12)
↑ AUC by 75% ↓ AUC by 50% Monitor for rifabutin associated
adverse events. Reduce dose or
suspend use of rifabutin if toxicity
is suspected. Alternative treatment
for clarithromycin should be considered
when treating patients receiving rifabutin
ANTI-TB (Tuberculosis)
Ethambutol 1200 mg 300 mg QD
X 7 days
Healthy
subjects(10)
ND
Isoniazid 300 mg 300 mg QD
X 7 days
Healthy
subjects (6)
ND
OTHER
Methadone 20 to 100
mg QD
300 mg QD
X 13 days
HIV-infected
patients (24)
ND
Ethinylestradiol (EE)/
Norethindrone (NE)
35 mg EE /
1 mg NE
X 21 days
300 mg QD
X 10 days
Healthy female
subjects (22)
ND EE: ↓ AUC by 35%,
↓ C max by 20%
NE: ↓ AUC by 46%
Patients should be advised to use
additional or alternative methods
of contraception.
Theophylline 5 mg/kg 300 mg
X 14 days
Healthy
subjects (11)
ND


Table name:
Table 18. Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
*Change relative to reference
Coadministered Drug
 
Dosing Schedule
Effect on Active Moiety
(Risperidone + 9- Hydroxy-
Risperidone (Ratio*)
Risperidone Dose
Recommendation
Coadministered Drug
Risperidone
AUC
C max
Enzyme (CYP2D6) inhibitors
 
 
 
 
Fluoxetine
20 mg/day
2 or 3 mg twice daily
1.4
1.5

Re-evaluate dosing.
Do not exceed 8 mg/day
Paroxetine
10 mg/day
4 mg/day
1.3
-

Re-evaluate dosing.
Do not exceed 8 mg/day
20 mg/day
4 mg/day
1.6
-
40 mg/day
4 mg/day
1.8
-
Enzyme (CYP3A/ PgP inducers) Inducers
 
 
 
 
 
Carbamazepine
573 ± 168 mg/day
 
3 mg twice daily
 
0.51
 
0.55
 

Titrate dose upwards.
Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) inhibitors
 
 
 
 
 
Ranitidine
150 mg twice daily
1 mg single dose
1.2
1.4
Dose adjustment not needed
Cimetidine
400 mg twice daily
1 mg single dose
1.1
1.3
Dose adjustment not needed
Erythromycin
500 mg four times daily
1 mg single dose
1.1
0.94
Dose adjustment not needed
Other Drugs
 
 
 
 
 
Amitriptyline
50 mg twice daily
3 mg twice daily
1.2
1.1
Dose adjustment not Needed


Table name:
Table 3: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 10 and 20 mg in BPH patients on stable alpha-blocker therapy with tamsulosin 0.4 or 0.8 mg daily (Study 2)
Vardenafil 10 mg
Placebo-subtracted
Vardenafil 20 mg
Placebo-subtracted
Standing SBP -4 (-6.8, -0.3) -4 (-6.8, -1.4)
Supine SBP -5 (-8.2, -0.8) -4 (-6.3, -1.8)


Table name:
Drug Description
Heparin Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients
Pyrazinamide Inhibits pyrazinamide-induced hyperuricemia
Uricosuric Agents Effect of probenecid, sulfinpyrazone and phenylbutazone inhibited


Table name:
Factors
Dosage Adjustment of Aripiprazole tablets
Known CYP2D6 Poor Metabolizers
Administer half of usual dose
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors
Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors
Administer half of usual dose
Strong CYP2D6 and CYP3A4 inhibitors
Administer a quarter of usual dose
Strong CYP3A4 inducers
Double usual dose over 1 to 2 weeks


Table name:
Concomitant Drug Name or Drug Class
Clinical Rationale
Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) 
The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].
With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)
The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].
With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Antihypertensive Drugs
Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.
Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.9)]. 
Benzodiazepines (e.g., lorazepam)
The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.9)]
Monitor sedation and blood pressure. Adjust dose accordingly.


Table name:
Bleeding times
Clinical Impact: Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention: This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact: The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention: Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact: Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention: This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.


Table name:
Concomitant Drug
Effect on Concentration of Lamotrigine or Concomitant Drug
Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel
↓ lamotrigine
 
↓ levonorgestrel
Decreased lamotrigine concentrations approximately 50%.
Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide
↓ lamotrigine
 
 
? carbamazepine epoxide
Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
May increase carbamazepine epoxide levels.
Lopinavir/ritonavir
↓ lamotrigine
Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir
↓ lamotrigine
Decreased lamotrigine AUC approximately 32%.
Phenobarbital/Primidone
↓ lamotrigine
Decreased lamotrigine concentration approximately 40%.
Phenytoin
↓ lamotrigine
Decreased lamotrigine concentration approximately 40%.
Rifampin
↓ lamotrigine
Decreased lamotrigine AUC approximately 40%.
Valproate
↑ lamotrigine
 
? valproate
Increased lamotrigine concentrations slightly more than 2-fold.
There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.


Table name:
Antibiotics Anticonvulsants Other Drugs/Dietary Supplements
nafcillin
rifampin
carbamazepine
oxcarbazepine
phenobarbital
phenytoin
bosentan
octreotide
orlistat
sulfinpyrazone
St. John's Wort
terbinafine
ticlopidine


Table name:
Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.11, 7.3)


Table name:
Drug Interactions Associated with Increased Risk of  Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice Avoid grapefruit juice


Table name:
a Should be administered at least 4 hours prior to WELCHOL
b No significant alteration of warfarin drug levels with warfarin and WELCHOL coadministration in an in vivo study which did not evaluate warfarin pharmacodynamics (INR). [See Post-marketing Experience (6.2)]
c Cyclosporine levels should be monitored and, based on theoretical grounds, cyclosporine should be administered at least 4 hours prior to WELCHOL.
d Patients receiving concomitant metformin ER and colesevelam should be monitored for clinical response as is usual for the use of anti-diabetes drugs.
Table 4 Drugs Tested in In Vitro Binding or In Vivo Drug Interaction Testing or With Post-Marketing Reports
Drugs with a known interaction with colesevelam:
Decrease in exposure of coadministered drug
cyclosporinec, glimepiridea, glipizidea, glyburidea,
levothyroxinea, olmesartan medoxomila, and oral
contraceptives containing ethinyl estradiol and
norethindronea
Drugs with a known interaction with colesevelam:
Increase in exposure of coadministered drug
metformin extended release (ER)d
Drug(s) with postmarketing reports consistent with
potential drug-drug interactions when
coadministered with WELCHOL
phenytoina, warfarinb
Drugs that do not interact with colesevelam based
on in vitro or in vivo testing
aspirin, atenolol, cephalexin, ciprofloxacin,
digoxin, enalapril, fenofibrate, lovastatin,
metformin, metoprolol, phenytoina, pioglitazone,
rosiglitazone, quinidine, repaglinide, sitagliptin,
valproic acid, verapamil, warfarinb


Table name:
Substance Average Duration of Effect
Anti-thyroid drugs
e.g.,
carbimazole, propylthiouracil
5 days
Natural or synthetic thyroid hormone
  e.g.,
thyroxine
  tri-iodothyronine
4 weeks
2 weeks
Iodine-containing medications
e.g., amiodarone expectorants, vitamins
4 weeks
2 weeks
Topical iodide 1-9 months
X-ray contrast agents
iodine-containing agents
Up to 1 year
Other  drugs
anticoagulants, antihistamines
corticosteroids, sulfonamides
tolbutamide, perchlorate
phenylbutazone
lithium
1 week
1 week
1 week
1-2 weeks
4 weeks


Table name:
Drugs that Affect Renal Function A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDS], COX-2 inhibitors may impair the excretion of digoxin.
Antiarrthymics Dofetilide Concomitant administration with digoxin was associated with a higher rate of torsades de pointes
Sotalol Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
Dronedarone Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone Analog Teriparatide Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement Thyroid Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics Epinephrine
Norepinephrine     
Dopamine
Can increase the risk of cardiac arrhythmias
Neuromuscular Blocking Agents      Succinylcholine May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.
Supplements Calcium If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.


Table name:
Interacting Drug Interaction
Multivalent cation-containing products
including antacids, metal cations or didanosine
Absorption of levofloxacin is decreased when the tablet
formulation is taken within 2 hours of this product. (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time,
INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.11, 7.3)


Table name:
Table 7: Effect of Voriconazole on Pharmacokinetics of Other Drugs [see Clinical Pharmacology (12.3)]
*  Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects
** Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects
*** Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for 4 days voriconazole to subjects receiving a methadone maintenance dose (30-100 mg q24h)
****  Non-Steroidal Anti-Inflammatory Drug
***** Non-Nucleoside Reverse Transcriptase Inhibitors
Drug/Drug Class
(Mechanism of Interaction by Voriconazole)

Drug Plasma Exposure
(Cmax and AUCτ)
Recommendations for Drug Dosage Adjustment/Comments
Sirolimus*
(CYP3A4 Inhibition)
Significantly Increased
Contraindicated
Rifabutin*
(CYP3A4 Inhibition)
Significantly Increased
Contraindicated
Efavirenz (400 mg q24h)** (CYP3A4 Inhibition)
 
Efavirenz (300 mg q24h)** (CYP3A4 Inhibition)
 
Significantly  Increased
 
 
Slight Increase inAUCτ
Contraindicated
 
 
When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)** (CYP3A4 Inhibition)

Low-dose Ritonavir (100 mg q12h)**
No Significant Effect of Voriconazole on Ritonavir Cmax or AUCτ

Slight Decrease in Ritonavir Cmax and AUCτ
Contraindicated because of significant reduction of voriconazole Cmax and AUCτ


Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole Cmax and AUCτ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (CYP3A4 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased
Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids
(CYP450 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased
Contraindicated
Cyclosporine*
(CYP3A4 Inhibition)
AUCτ Significantly Increased; No Significant Effect on Cmax
When initiating therapy with voriconazole tablets in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When voriconazole tablets are discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
Methadone*** (CYP3A4 Inhibition)
Increased
Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl
(CYP3A4 Inhibition)
Increased
Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazoletablets. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7)]
Alfentanil
(CYP3A4 Inhibition)
Significantly Increased
Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with voriconazole tablet. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [see Drug Interactions (7)].
Oxycodone
(CYP3A4 Inhibition)
Significantly Increased
Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazoletablets. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7)].
NSAIDs**** including ibuprofen and diclofenac
(CYP2C9 Inhibition) 
Increased
Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed [see Drug Interactions (7)].
Tacrolimus*
(CYP3A4 Inhibition) 
Significantly Increased 
When initiating therapy with voriconazole tablets in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazoletablets are discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin*
(CYP2C9 Inhibition)
Significantly Increased
Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone
(CYP3A4 Inhibition)**
Increased
Monitoring for adverse events related to oral contraceptives is recommended during coadministration.
Warfarin*
(CYP2C9 Inhibition)
Prothrombin Time Significantly Increased
Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed.
Omeprazole*
(CYP2C19/3A4 Inhibition)
Significantly Increased
When initiating therapy with voriconazoletablets in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors
(CYP3A4 Inhibition)
In Vivo Studies Showed No Significant Effects on Indinavir Exposure
 
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)
No dosage adjustment for indinavir when coadministered with voriconazole tablets
 
 
Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors
Other NNRTIs***** (CYP3A4 Inhibition)
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity related to NNRTI
Benzodiazepines
(CYP3A4 Inhibition)
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.
HMG-CoA Reductase Inhibitors (Statins)
(CYP3A4 Inhibition)
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers
(CYP3A4 Inhibition)
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics
(CYP2C9 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased
Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids (CYP3A4 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased
Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed.
Everolimus
(CYP3A4 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased
Concomitant administration of
voriconazole and everolimus is not recommended. 


Table name:
Table 1: Clinically Significant Drug Interactions with Naproxen
  Drugs That Interfere with Hemostasis
  Clinical Impact:   Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
  Intervention:  Monitor patients with concomitant use of naproxen tablets with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
  Aspirin
  Clinical Impact:  Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
  Intervention:  Concomitant use of naproxen tablets and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen tablets are not a substitute for low dose aspirin for cardiovascular protection.
  ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
  Clinical Impact:   NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
  Intervention:   During concomitant use of naproxen tablets and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of naproxen tablets and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
  Diuretics
  Clinical Impact:  Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
  Intervention  During concomitant use of naproxen tablets with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
  Digoxin
  Clinical Impact:  The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
  Intervention:  During concomitant use of naproxen tablets and digoxin, monitor serum digoxin levels.
  Lithium
  Clinical Impact:  NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
  Intervention:  During concomitant use of naproxen tablets and lithium, monitor patients for signs of lithium toxicity.
  Methotrexate
  Clinical Impact:  Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
  Intervention:  During concomitant use of naproxen tablets and methotrexate, monitor patients for methotrexate toxicity.
  Cyclosporine
  Clinical Impact:  Concomitant use of naproxen tablets and cyclosporine may increase cyclosporine’s nephrotoxicity.
  Intervention:  During concomitant use of naproxen tablets and cyclosporine, monitor patients for signs of worsening renal function.
  NSAIDs and Salicylates
  Clinical Impact:  Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
  Intervention:  The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
  Pemetrexed
  Clinical Impact:  Concomitant use of naproxen tablets and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
  Intervention:  During concomitant use of naproxen tablets and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
  Antacids and Sucralfate
  Clinical Impact:  Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
  Intervention:  Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen tablets are not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen tablets are not recommended.
  Cholestyramine
  Clinical Impact:  Concomitant administration of cholestyramine can delay the absorption of naproxen.
  Intervention:  Concomitant administration of cholestyramine with naproxen tablets are not recommended.
  Probenecid
  Clinical Impact:  Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
  Intervention:  Patients simultaneously receiving naproxen tablets and probenecid should be observed for adjustment of dose if required.
  Other albumin-bound drugs
  Clinical Impact:  Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
  Intervention:  Patients simultaneously receiving naproxen tablets and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.


Table name:
Table 4 Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table 5 for Magnitude of Interaction.
Drug Name
Effect on Concentration of Nevirapine or Concomitant Drug
Clinical Comment
HIV Antiviral Agents: Protease Inhibitors (PIs)
Atazanavir/Ritonavir*
↓ Atazanavir
↑ Nevirapine
Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures.
Fosamprenavir*
↓Amprenavir
↑Nevirapine
Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.
Fosamprenavir/Ritonavir*
↓Amprenavir
↑Nevirapine
No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied.
Indinavir*
↓ Indinavir
The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established.
Lopinavir/Ritonavir*
↓Lopinavir
Dosing in adult patients:
 
A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.
 
Dosing in pediatric patients:
 
Please refer to the Kaletra® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. 
Nelfinavir*
↓ Nelfinavir M8 Metabolite
↓ Nelfinavir Cmin
The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established.
Saquinavir/ritonavir
The interaction between nevirapine and saquinavir/ritonavir has not been evaluated
The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz*
↓ Efavirenz 
The appropriate doses of these combinations with respect to safety and efficacy have not been established.
Delavirdine
Etravirine
Rilpivirine
 
Plasma concentrations may be altered.  Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial.
Hepatitis C Antiviral Agents
Boceprevir
Plasma concentrations of boceprevir may be decreased due to induction of CYP3A4/5 by nevirapine.
Nevirapine and boceprevir should not be coadministered because decreases in boceprevir plasma concentrations may result in a reduction in efficacy.
Telaprevir
Plasma concentrations of telaprevir may be decreased due to induction of CYP3A4 by nevirapine and plasma concentrations of nevirapine may be increased due to inhibition of CYP3A4 by telaprevir.
Nevirapine and telaprevir should not be coadministered because changes in plasma concentrations of nevirapine, telaprevir, or both may result in a reduction in telaprevir efficacy or an increase in nevirapine-associated adverse events.
Other Agents
Analgesics:
Methadone*
 
↓Methadone
 
Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Antiarrhythmics:
Amiodarone, disopyramide, lidocaine
 
Plasma concentrations may be decreased.
 
Appropriate doses for this combination have not been established.
Antibiotics:
Clarithromycin*
 
↓Clarithromycin
↑14-OH clarithromycin
 
Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium- intracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.
Rifabutin*
↑Rifabutin
Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.
Rifampin*
↓Nevirapine
Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Anticonvulsants:
Carbamazepine, clonazepam, ethosuximide
 
Plasma concentrations of nevirapine and the anticonvulsant may be decreased.
 
Use with caution and monitor virologic response and levels of anticonvulsants.
Antifungals:
Fluconazole*
 
↑Nevirapine
 
Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events.
Ketoconazole*
↓Ketoconazole
Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.
Itraconazole
↓Itraconazole
Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug.
Antithrombotics:
Warfarin
 
Plasma concentrations may be increased.
 
Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.
Calcium channel blockers:
Diltiazem, nifedipine, verapamil
 
Plasma concentrations may be decreased.
 
Appropriate doses for these combinations have not been established.
Cancer chemotherapy:
Cyclophosphamide
 
Plasma concentrations may be decreased.
 
Appropriate doses for this combination have not been established.
Ergot alkaloids:
Ergotamine
 
Plasma concentrations may be decreased.
 
Appropriate doses for this combination have not been established.
Immunosuppressants:
Cyclosporine, tacrolimus, sirolimus
 
Plasma concentrations may be decreased.
 
Appropriate doses for these combinations have not been established.
Motility agents:
Cisapride
 
Plasma concentrations may be decreased.
 
Appropriate doses for this combination have not been established.
Opiate agonists:
Fentanyl
 
Plasma concentrations may be decreased.
 
Appropriate doses for this combination have not been established.
Oral contraceptives:
Ethinyl estradiol and Norethindrone*
 
↓Ethinyl estradiol
↓Norethindrone
 
Despite lower ethinyl estradiol and norethindrone exposures when coadministered with nevirapine, literature reports suggest that nevirapine has no effect on pregnancy rates among HIV-infected women on combined oral contraceptives. When coadministered with nevirapine, no dose adjustment of ethinyl estradiol or norethindrone is needed when used in combination for contraception.

When these oral contraceptives are used for hormonal regulation during nevirapine therapy, the therapeutic effect of the hormonal therapy should be monitored.
* The interaction between nevirapine and the drug was evaluated in a clinical study. All other drug interactions shown are predicted.


Table name:
Antibiotics Anticonvulsants Other Drugs/Dietary Supplements
nafcillin carbamazepine bosentan terbinafine
rifampin oxcarbazepine octreotide ticlopidine
phenobarbital orlistat St. John's Wort
phenytoin sulfinpyrazone


Table name:
Bleeding times
Clinical Impact: Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention: This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact: The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention: Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact: Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention: This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.


Table name:
DRUG DESCRIPTION OF INTERACTION
Heparin Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients.
Pyrazinamide Inhibits pyrazinamide-induced hyperuricemia.
Uricosuric Agents Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited.


Table name:
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Drug Interactions Associated with Increased
Risk of Myopathy/Rhabdomyolysis (2.2, 4, 5.2, 7.1, 7.2, 7.3, 7.4, 12.3)
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g.,
itraconazole,
ketoconazole,
posaconazole,
erythromycin,
clarithromycin,
telithromycin, HIV protease inhibitors,
boceprevir,
telaprevir,
nefazodone),
gemfibrozil, cyclosporine,
danazol,
verapamil, diltiazem
Contraindicated with SIMCOR
Amiodarone, amlodipine, ranolazine Do not exceed 1000/20 mg SIMCOR daily
Grapefruit juice Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Inhibitors of CYP2D6
Clinical Impact:
The concomitant use of tramadol hydrochloride and acetaminophen and CYP2D6 inhibitors may result in an increase in the plasma concentration of tramadol and a decrease in the plasma concentration of M1, particularly when an inhibitor is added after a stable dose of tramadol hydrochloride and acetaminophen is achieved. Since M1 is a more potent µ-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome.

After stopping a CYP2D6 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease and the M1 plasma concentration will increase which could increase or prolong therapeutic effects but also increase adverse reactions related to opioid toxicity, and may cause potentially fatal respiratory depression  [see Clinical Pharmacology (12.3)].
Intervention:
If concomitant use of a CYP2D6 inhibitor is necessary, follow patients closely for adverse reactions including opioid withdrawal, seizures and serotonin syndrome.

If a CYP2D6 inhibitor is discontinued, consider lowering tramadol hydrochloride and acetaminophen dosage until stable drug effects are achieved. Follow patients closely for adverse events including respiratory depression and sedation.
Examples
Quinidine, fluoxetine, paroxetine and bupropion
Inhibitors of CYP3A4
Clinical Impact:
The concomitant use of tramadol hydrochloride and acetaminophen and CYP3A4 inhibitors can increase the plasma concentration of tramadol and may result in a greater amount of metabolism via CYP2D6 and greater levels of M1. Follow patients closely for increased risk of serious adverse events including seizures and serotonin syndrome, and adverse reactions related to opioid toxicity including potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of tramadol hydrochloride and acetaminophen is achieved.
 
After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease [see Clinical Pharmacology  (12.3)], resulting in decreased opioid efficacy and possibly signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol.
Intervention:
If concomitant use is necessary, consider dosage reduction of tramadol hydrochloride and acetaminophen until stable drug effects are achieved. Follow patients closely for seizures and serotonin syndrome, and signs of respiratory depression and sedation at frequent intervals.
 
If a CYP3A4 inhibitor is discontinued, consider increasing the tramadol hydrochloride and acetaminophen dosage until stable drug effects are achieved and follow patients for signs and symptoms of opioid withdrawal.
Examples
Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir)
CYP3A4 Inducers
Clinical Impact:
The concomitant use of tramadol hydrochloride and acetaminophen and CYP3A4 inducers can decrease the plasma concentration of tramadol [see Clinical Pharmacology  (12.3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to tramadol.
 
After stopping a CYP3A4 inducer, as the effects of the inducer decline, the tramadol plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression, seizures and serotonin syndrome.
Intervention:
If concomitant use is necessary, consider increasing the tramadol hydrochloride and acetaminophen dosage until stable drug effects are achieved. Follow patients for signs of opioid withdrawal.
 
If a CYP3A4 inducer is discontinued, consider tramadol hydrochloride and acetaminophen dosage reduction and monitor for seizures and serotonin syndrome, and signs of sedation and respiratory depression.
 
Patients taking carbamazepine, a CYP3A4 inducer, may have a significantly reduced analgesic effect of tramadol. Because carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of tramadol hydrochloride and acetaminophen and carbamazepine is not recommended.
Examples:
Rifampin, carbamazepine, phenytoin
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact:
Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:
Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.6)].
Examples:
Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact:
The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention:
If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue tramadol hydrochloride and acetaminophen if serotonin syndrome is suspected.
Examples:
Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:
MAOI interactions with opioids may manifest as serotonin syndrome [see Warnings and Precautions (5.7)] or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)].
Intervention:
Do not use tramadol hydrochloride and acetaminophen in patients taking MAOIs or within 14 days of stopping such treatment.
Examples:
phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:
May reduce the analgesic effect of tramadol hydrochloride and acetaminophen and/or precipitate withdrawal symptoms.
Intervention:
Avoid concomitant use.
Examples:
butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact:
Tramadol may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:
Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of tramadol hydrochloride and acetaminophen and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact:
Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:
Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:
The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:
Monitor patients for signs of urinary retention or reduced gastric motility when tramadol hydrochloride and acetaminophen is used concomitantly with anticholinergic drugs.
Digoxin
Clinical Impact:
Post-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity.
Intervention:
Follow patients for signs of digoxin toxicity and adjust dosage of digoxin as needed.
Warfarin
Clinical Impact:
Post-marketing surveillance of tramadol has revealed rare reports of alteration of warfarin effect, including elevation of prothrombin times.
Intervention:
Monitor the prothrombin time of patients on warfarin for signs of an interaction and adjust the dosage of warfarin as needed.


Table name:
Table 5. Drugs That May Decrease Conversion of T4 to T3
Potential impact: Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased.
Drug or Drug Class Effect
Beta-adrenergic antagonists
(e.g., Propranolol > 160 mg/day)
In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change, TSH levels remain normal, and patients are clinically euthyroid. Actions of particular beta-adrenergic antagonists may be impaired when a hypothyroid patient is converted to the euthyroid state.
Glucocorticoids
(e.g., Dexamethasone > 4 mg/day)
Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (See above).
Other drugs:
Amiodarone
Amiodarone inhibits peripheral conversion of levothyroxine (T4) to triiodothyronine (T3) and may cause isolated biochemical changes (increase in serum free-T4, and decreased or normal free-T3) in clinically euthyroid patients.


Table name:
Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme
Inhibitors
Inducers
CYP2C9 
amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast
aprepitant, bosentan, carbamazepine, phenobarbital, rifampin 
CYP1A2 
acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton
montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking 
CYP3A4 
alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton
armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide 


Table name:
Antibiotics Anticonvulsants Other Drugs/DietarySupplements
nafcillin carbamazepine bosentan  St. John’s Wort
rifampin oxcarbazepine octreotide
phenobarbital orlistat
phenytoin sulfinpyrazone
terbinafine
ticlopidine


Table name:
Concomitant Drug Name or Drug Class
Clinical Rationale
Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine)
The concomitant use of aripiprazole tablets with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole tablets alone [seeCLINICALPHARMACOLOGY( 12.3)].
Withconcomitant use of aripiprazole tablets with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole tablets dosage [see DOSAGEANDADMINISTRATION (2.7)].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)
The concomitant use of aripiprazole tablets and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole tablets alone [see CLINICALPHARMACOLOGY (12.3)].
Withconcomitant use of aripiprazole tablets with a strong CYP3A4 inducer, consider increasing the aripiprazole tablets dosage [see DOSAGE ANDADMINISTRATION( 2.7)].
AntihypertensiveDrugs
Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.
Monitor bloodpressure and adjust dose accordingly [seeWARNINGS AND PRECAUTIONS (5.8)].
Benzodiazepines(e.g., lorazepam)
The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that
observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [seeWARNINGSANDPRECAUTIONS  (5.8)]
Monitor sedation and blood pressure. Adjust dose accordingly.


Table name:
AED Coadministered
AED Concentration
Topiramate 
Concentration

a= Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. b= Is not administered but is an active metabolite of carbamazepine. NC = Less than 10% change in plasma concentration. NE = Not Evaluated
Phenytoin
NC or 25% increasea
48% decrease
Carbamazepine (CBZ)
NC
40% decrease
CBZ epoxideb
NC
NE
Valproic acid
11% decrease
14% decrease
Phenobarbital
NC 
NE
Primidone
NC
NE
Lamotrigine
NC at TPM doses up to 400 mg/day
13% decrease



Table name:
Table 6: Clinically Significant Drug Interactions with Paricalcitol
CYP3A Inhibitors
Clinical Impact
Paricalcitol is partially metabolized by CYP3A. Hence, exposure of paricalcitol will increase upon coadministration with strong CYP3A inhibitors such as but not limited to: boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole.
Intervention
Dose adjustment of paricalcitol capsules may be necessary. Monitor closely for iPTH and serum calcium concentrations, if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor.
Cholestyramine
Clinical Impact
Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of paricalcitol.
Intervention
Recommend to take paricalcitol capsules at least 1 hour before or 4 to 6 hours after taking cholestyramine (or at as great an interval as possible) to avoid impeding absorption of paricalcitol.
Mineral Oil
Clinical Impact
Mineral oil or other substances that may affect absorption of fat may influence the absorption of paricalcitol.
Intervention
Recommend to take paricalcitol capsules at least 1 hour before or 4 to 6 hours after taking mineral oil (or at as great an interval as possible) to avoid affecting absorption of paricalcitol.


Table name:
Table 8: Clinically Significant Drug Interactions with Clarithromycin
   Drugs That Are Affected By Clarithromycin
 Drug(s) with Pharmacokinetics Affected by Clarithromycin  Recommendation  Comments
Antiarrhythmics:
   Disopyramide
   Quinidine
   Dofetilide
   Amiodarone
   Sotalol
   Procainamide
 Not
Recommended
Disopyramide, Quinidine: There have been postmarketing reports of torsades de pointes
occurring with concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QTc prolongation during coadministration of clarithromycin with these drugs [see Warnings and Precautions (5.3)].
Serum concentrations of these medications should also be monitored. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with disopyramide and quinidine.
There have been postmarketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide. Therefore, blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide.
 Digoxin  Use With Caution Digoxin: Digoxin is a substrate for P-glycoprotein (Pgp) and clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are coadministered, inhibition of Pgp by clarithromycin may lead to increased exposure of digoxin. Elevated digoxin serum concentrations in patients receiving clarithromycin and digoxin concomitantly have been reported in postmarketing surveillance. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Monitoring of serum digoxin concentrations should be considered, especially for patients with digoxin concentrations in the upper therapeutic range.
Oral Anticoagulants:
   Warfarin
 Use With Caution Oral anticoagulants: Spontaneous reports in the postmarketing period suggest that concomitant administration of clarithromycin and oral anticoagulants may potentiate the effects of the oral anticoagulants. Prothrombin times should be carefully monitored while patients are receiving clarithromycin and oral anticoagulants simultaneously [see Warnings and Precautions (5.4)].
Antiepileptics:
   Carbamazepine
 Use With Caution Carbamazepine: Concomitant administration of single doses of clarithromycin and carbamazepine has been shown to result in increased plasma concentrations of carbamazepine. Blood level monitoring of carbamazepine may be considered. Increased serum concentrations of carbamazepine were observed in clinical trials with clarithromycin. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with carbamazepine.
Antifungals:    Itraconazole    Fluconazole  Use With Caution No Dose Adjustment Itraconazole: Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when administered concomitantly (see also Itraconazole under “Drugs That Affect Clarithromycin” in the table below). Clarithromycin may increase the plasma concentrations of itraconazole. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions. Fluconazole: [see Pharmacokinetics (12.3)]
 Anti-Gout Agents:
   Colchicine (in    patients
   with renal or    hepatic
   impairment)
   Colchicine (in    patients
   with normal renal    and
   hepatic function)
 Contraindicated Use With Caution Colchicine: Colchicine is a substrate for both
CYP3A and the efflux transporter, P-glycoprotein
(Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. The dose of colchicine should be reduced when co-administered
with clarithromycin in patients with normal renal
and hepatic function [see Contraindications (4.4) and Warnings and Precautions (5.4)].
Antipsychotics:
   Pimozide
   Quetiapine
 Contraindicated Pimozide: [See Contraindications (4.2)] Quetiapine: Quetiapine is a substrate for CYP3A4, which is inhibited by clarithromycin. Coadministration with clarithromycin could result in increased quetiapine exposure and possible quetiapine related toxicities. There have been postmarketing reports of somnolence, orthostatic hypotension, altered state of consciousness, neuroleptic malignant syndrome, and QT prolongation during concomitant administration. Refer to quetiapine prescribing information for recommendations on dose reduction if coadministered with CYP3A4 inhibitors such as clarithromycin.
 Antispasmodics:
   Tolterodine    (patients    deficient in    CYP2D6    activity)
 Use With Caution Tolterodine: The primary route of metabolism for tolterodine is via CYP2D6. However, in a subset of the population devoid of CYP2D6, the identified pathway of metabolism is via CYP3A. In this population subset, inhibition of CYP3A results in significantly higher serum concentrations of tolterodine. Tolterodine 1 mg twice daily is recommended in patients deficient in CYP2D6 activity (poor metabolizers) when co-administered with clarithromycin.
Antivirals:   Atazanavir    Saquinavir (in    patients    with    decreased renal    function)    Ritonavir    Etravirine    Maraviroc    Boceprevir (in patients    with    normal renal    function)   Zidovudine  Use With Caution No Dose Adjustment Atazanavir: Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction (see Atazanavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)]. Saquinavir: Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A and there is evidence of a bi-directional drug interaction (see Saquinavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)]. Ritonavir, Etravirine: (see Ritonavir and Etravirine under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)]. Maraviroc: Clarithromycin may result in increases in maraviroc exposures by inhibition of CYP3A metabolism. See Selzentry® prescribing information for dose recommendation when given with strong CYP3A inhibitors such as clarithromycin. Boceprevir: Both clarithromycin and boceprevir are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when coadministered. No dose adjustments are necessary for patients with normal renal function (see Victrelis® prescribing information). Zidovudine: Simultaneous oral administration of clarithromycin immediate-release tablets and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine concentrations. Administration of clarithromycin and zidovudine should be separated by at least two hours [see Pharmacokinetics (12.3)]. The impact of co-administration of clarithromycin extended-release tablets or granules and zidovudine has not been evaluated.
Calcium Channel Blockers:
   Verapamil   Amlodipine    Diltiazem    Nifedipine
 Use With Caution Verapamil: Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent verapamil, [see Warnings and Precautions (5.4)]. Amlodipine, Diltiazem: [See Warnings and Precautions (5.4)]
Nifedipine: Nifedipine is a substrate for CYP3A. Clarithromycin and other macrolides are known to inhibit CYP3A. There is potential of CYP3A-mediated interaction between nifedipine and clarithromycin. Hypotension and peripheral edema were observed when clarithromycin was taken concomitantly with nifedipine [see Warnings and Precautions (5.4)].
Ergot Alkaloids:
   Ergotamine
   Dihydroergotamine
 Contraindicated Ergotamine, Dihydroergotamine: Postmarketing
reports indicate that coadministration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system [see Contraindications (4.6)].
Gastroprokinetic
Agents:
   Cisapride
 Contraindicated Cisapride: [See Contraindications (4.2)]
HMG-CoA Reductase Inhibitors:   Lovastatin
   Simvastatin
   Atorvastatin
   Pravastatin
   Fluvastatin
Contraindicated Use With Caution No Dose Adjustment Lovastatin, Simvastatin, Atorvastatin, Pravastatin, Fluvastatin: [See Contraindications (4.5) and Warnings and Precautions (5.4)]
Hypoglycemic Agents:   Nateglinide
   Pioglitazone
   Repaglinide
   Rosiglitazone
   Insulin
 Use With Caution Nateglinide, Pioglitazone, Repaglinide, Rosiglitazone: [See Warnings and Precautions (5.4) and Adverse Reactions (6.2)] Insulin: [See Warnings and Precautions (5.4) and Adverse Reactions (6.2)]
Immunosuppressants:    Cyclosporine    Tacrolimus  Use With Caution Cyclosporine: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with cyclosporine. Tacrolimus: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with tacrolimus.
Phosphodiesterase inhibitors:    Sildenafil
   Tadalafil
   Vardenafil
 Use With Caution Sildenafil, Tadalafil, Vardenafil: Each of these phosphodiesterase inhibitors is primarily metabolized by CYP3A, and CYP3A will be inhibited by concomitant administration of clarithromycin. Co-administration of clarithromycin with sildenafil, tadalafil, or vardenafil will result in increased exposure of these phosphodiesterase inhibitors. Co-administration of these phosphodiesterase inhibitors with clarithromycin is not recommended. Increased systemic exposure of these drugs may occur with clarithromycin; reduction of dosage for phosphodiesterase inhibitors should be considered (see their respective prescribing information).
Proton Pump Inhibitors:
   Omeprazole
 No Dose Adjustment Omeprazole: The mean 24 hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when coadministered with clarithromycin as a result of increased omeprazole exposures [see Pharmacokinetics (12.3)] (see also Omeprazole under “Drugs That Affect Clarithromycin” in the table below).
Xanthine Derivatives:
   Theophylline
 Use With Caution Theophylline: Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serum theophylline concentrations [see Pharmacokinetics (12.3)]. Monitoring of serum theophylline concentrations should be considered for patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range.
Triazolobenzodiazepines and Other Related Benzodiazepines:    Midazolam    Alprazolam    Triazolam    Temazepam
   Nitrazepam
   Lorazepam
Use With Caution No Dose Adjustment Midazolam: When oral midazolam is coadministered with clarithromycin, dose adjustments may be necessary and possible prolongation and intensity of effect should be anticipated [see Warnings and Precautions (5.4) and Pharmacokinetics (12.3)]. Triazolam, Alprazolam: Caution and appropriate dose adjustments should be considered when triazolam or alprazolam is co-administered with clarithromycin. There have been postmarketing reports of drug interactions and central nervous system (CNS) effects (e.g., somnolence and confusion) with the concomitant use of clarithromycin and triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested. In postmarketing experience, erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines. Temazepam, Nitrazepam, Lorazepam: For benzodiazepines which are not metabolized by CYP3A (e.g., temazepam, nitrazepam, lorazepam), a clinically important interaction with clarithromycin is unlikely.
Cytochrome P450 Inducers:    Rifabutin  Use With Caution Rifabutin: Concomitant administration of rifabutin and clarithromycin resulted in an increase in rifabutin, and decrease in clarithromycin serum levels together with an increased risk of uveitis (see Rifabutin under “Drugs That Affect Clarithromycin” in the table below).
Other Drugs Metabolized by CYP3A:   Alfentanil
   Bromocriptine
   Cilostazol
   Methylprednisole
   Vinblastine
   Phenobarbital
   St. John’s Wort
 Use With Caution There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with alfentanil, methylprednisolone, cilostazol, bromocriptine, vinblastine, phenobarbital, and St. John’s Wort.
Other Drugs Metabolized by CYP450 Isoforms Other than CYP3A:
   Hexobarbital
   Phenytoin
   Valproate
 Use With Caution There have been postmarketing reports of interactions of clarithromycin with drugs not thought to be metabolized by CYP3A, including hexobarbital, phenytoin, and valproate.
   Drugs that Affect Clarithromycin
 Drug(s) that Affect the Pharmacokinetics of Clarithromycin  Recommendation  Comments
Antifungals:
   Itraconazole
 Use With Caution Itraconazole: Itraconazole may increase the plasma concentrations of clarithromycin. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions (see also Itraconazole under “Drugs That Are Affected By Clarithromycin” in the table above).
Antivirals:
   Atazanavir
   Ritonavir (in patients with    decreased renal function)    Saquinavir (in patients with    decreased renal function)    Etravirine    Saquinavir (in    patients with    normal renal    function)        Ritonavir (in patients    with    normal renal    function)
 Use With Caution No Dose Adjustment Atazanavir: When clarithromycin is co-administered with atazanavir, the dose of clarithromycin should be decreased by 50% [see Clinical Pharmacology (12.3)]. Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is coadministered with atazanavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium complex. Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors. Ritonavir: Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with ritonavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium [see Pharmacokinetics (12.3)]. Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors. Saquinavir: When saquinavir is co-administered with ritonavir, consideration should be given to the potential effects of ritonavir on clarithromycin (refer to ritonavir above) [see Pharmacokinetics (12.3)]. Etravirine: Clarithromycin exposure was decreased by etravirine; however, concentrations of the active metabolite, 14-OH-clarithromycin, were increased. Because 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered; therefore alternatives to clarithromycin should be considered for the treatment of MAC.
Proton Pump Inhibitors:   Omeprazole  Use With Caution Omeprazole: Clarithromycin concentrations in the gastric tissue and mucus were also increased by concomitant administration of omeprazole [see Pharmacokinetics (12.3)].
Miscellaneous Cytochrome P450 Inducers:   Efavirenz
   Nevirapine
   Rifampicin
   Rifabutin
   Rifapentine
 Use With Caution Inducers of CYP3A enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine will increase the metabolism of clarithromycin, thus decreasing plasma concentrations of clarithromycin, while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. Alternative antibacterial treatment should be considered when treating patients receiving inducers of CYP3A. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with rifabutin (see Rifabutin under “Drugs That Are Affected By Clarithromycin” in the table above).


Table name:
Factors Dosage Adjustment of ABILIFY
Known CYP2D6 Poor Metabolizers Administer half of usual dose
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors Administer half of usual dose
Strong CYP2D6 and CYP3A4 inhibitors Administer a quarter of usual dose
Strong CYP3A4 inducers Double usual dose over 1 to 2 weeks


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function.
Drugs that may alter T4 and T3 serum transport - but FT4 concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin/Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens/Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non-Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4 . Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ³ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias
and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123 I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme
Inhibitors
Inducers
CYP2C9 
amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast
aprepitant, bosentan, carbamazepine, phenobarbital, rifampin 
CYP1A2 
acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton
montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking 
CYP3A4 
alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton
armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide 


Table name:
Interacting Drug Interaction
Drugs known to prolong QT interval (e.g., Class IA and Class III anti-arrhythmic agents). Quinine Sulfate Capsules prolong QT interval, ECG abnormalities including QT prolongation and Torsades de Pointes. Avoid concomitant use (5.3).
Other antimalarials (e.g., halofantrine, mefloquine). ECG abnormalities including QT prolongation. Avoid concomitant use (5.3, 7.2).
CYP3A4 inducers or inhibitors Alteration in plasma quinine concentration. Monitor for lack of efficacy or increased adverse events of quinine (7.1).
CYP3A4 and CYP2D6 substrates Quinine is an inhibitor of CYP3A4 and CYP2D6. Monitor for lack of efficacy or increased adverse events of the co-administered drug (7.2).
Digoxin Increased digoxin plasma concentration (5.8, 7.1).


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may
result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-
   containing radiographic
   contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which
may result in hyperthyroidism
Amiodarone
Iodide (including iodine-
containing Radiographic
contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase Drugs that may decrease
serum TBG concentration serum TBG concentration
Clofibrate Androgens / Anabolic Steroids
Estrogen-containing oral Asparaginase
   contraceptives Glucocorticoids
Estrogens (oral) Slow-Release Nicotinic Acid
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal
Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake
Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
NITROPRUSSIDE
Para-aminosalicylate sodium
Perphenazine
Resorcinol
 (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitors (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Interacting Drug Interaction
   Multivalent cation-containing products
   including antacids, metal cations or didanosine
   Absorption of levofloxacin is decreased when the tablet
   formulation  is taken within 2 hours of this product. (2.4, 7.1)
   Warfarin
   Effect may be enhanced. Monitor prothrombin time,
   INR, watch for bleeding (7.2)
   Antidiabetic agents
   Carefully monitor blood glucose (5.11, 7.3)


Table name:
Interacting Drug
Interaction
Multivalent cation-containing products including antacids,
metal cations or didanosine
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. ( 2.4, 7.1)
Warfarin
Effect may be enhanced. Monitor prothrombin
time, INR, watch for bleeding ( 7.2)
Antidiabetic agents
Carefully monitor blood glucose ( 5.12, 7.3)


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Factors
Dosage  Adjustments  for  Aripiprazole  Tablets
Known CYP2D6 Poor Metabolizers
Administer half of usual dose
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors
Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors
Administer half of usual dose
Strong CYP2D6 and CYP3A4
inhibitors
Administer a quarter of usual dose
Strong CYP3A4 inducers
Double usual dose over 1 to 2 weeks


Table name:
Oral hypoglycemics
Coumarin-type
anticoagulants
Phenytoin
Cyclosporine
Rifampin
Theophylline
Voriconazole
Tofacitinib
Oral Contraceptives
Hydrochlorothiazide
Amitriptyline, nortriptyline
Azithromycin
Calcium Channel Blockers
Cyclophosphamide
Quinidine
Halofantrine
Losartan
Non-steroidal
  anti-inflammatory drugs
Saquinavir
Vinca Alkaloids
Zidovudine
Terfenadine
Cisapride
Astemizole
Rifabutin
Tacrolimus
Short-acting
  benzodiazepines
Triazolam
Pimozide
Alfentanil
Amphotericin B
Carbamazepine
Celecoxib
Fentanyl
HMG-CoA reductase
  inhibitors
Methadone
Prednisone
Sirolimus
Vitamin A


Table name:
NA - Not available/reported
Digoxin concentrations increased > 50%
Digoxin Serum Concentration Increase Digoxin AUC Increase Recommendations
Amiodarone 70% NA Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin dose by approximately 30% to 50% and continue monitoring.
Captopril 58% 39%
Nitrendipine 57% 15%
Propafenone 35-85% NA
Quinidine 100% NA
Ranolazine 87% 88%
Ritonavir NA 86%
Verapamil 50-75% NA
Digoxin concentrations increased < 50%
Carvedilol 16% 14% Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin dose by approximately 15% to 30% and continue monitoring.
Diltiazem 20% NA
Nifedipine 45% NA
Rabeprazole 29% 19%
Telmisartan 20% NA
Digoxin concentrations increased, but magnitude is unclear
Alprazolam, Azithromycin, Clarithromycin, Cyclosporine, Diclofenac, Diphenoxylate, Epoprostenol, Erythromycin, Esomeprazole, Indomethacin, Itraconazole, Ketoconazole, Lansoprazole, Metformin, Omeprazole, Propantheline, Spironolactone, Tetracycline Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin concentrations decreased
Acarbose, Activated Charcoal, Albuterol, Antacids, Anticancer drugs, Cholestyramine, Colestipol, Exenatide, Kaolin-pectin, Meals High in Bran, Metoclpramide, Miglitol, Neomycin, Rifampin, Salbutamol, St.John's Wort, Sucralfate, Sulfasalazine Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20% to 40% as necessary.
No significant Digoxin concentration changes
Please refer to section 12.3 for a complete list of drugs which were studied but reported no significant changes on digoxin exposure. No additional actions are required.


Table name:
Bleeding Times
Clinical Impact: Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention: This effect should be kept in mind when bleeding times are determined.
Porter-Silber Test
Clinical Impact: The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention: Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary Assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact: Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention: This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.


Table name:
Table 6. Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Trials or Predicted Interactions [see Dosage and Administration (2)]
Concomitant Drug Class:
Drug Name
Effect on Concentration of Dolutegravir and/or Concomitant Drug Clinical Comment
HIV-1 Antiviral Agents
Non-nucleoside reverse transcriptase inhibitor: Etravirinea ↓Dolutegravir Use of TIVICAY with etravirine without coadministration of atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir is not recommended.
Non-nucleoside reverse transcriptase inhibitor: Efavirenza ↓Dolutegravir Adjust dose of TIVICAY to 50 mg twice daily for treatment-naïve and treatment-experienced, INSTI-naïve adult patients. In pediatric patients, increase the weight-based dose to twice daily (Table 2). Use alternative combinations that do not include metabolic inducers where possible for INSTI-experienced patients with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance.b
Non-nucleoside reverse transcriptase inhibitor: Nevirapine ↓Dolutegravir Avoid coadministration with nevirapine because there are insufficient data to make dosing recommendations.
Protease inhibitor: Fosamprenavir/ritonavira Tipranavir/ritonavira ↓Dolutegravir Adjust dose of TIVICAY to 50 mg twice daily for treatment-naïve and treatment-experienced, INSTI-naïve adult patients. In pediatric patients, increase the weight-based dose to twice daily (Table 2). Use alternative combinations that do not include metabolic inducers where possible for INSTI-experienced patients with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance.b
Other Agents
Carbamazepinea ↓Dolutegravir Adjust dose of TIVICAY to 50 mg twice daily in treatment-naïve or treatment-experienced, INSTI-naïve adult patients. In pediatric patients, increase the weight-based dose to twice daily (Table 2). Use alternative treatment that does not include carbamazepine where possible for INSTI-experienced patients with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance.b
Oxcarbazepine
Phenytoin
Phenobarbital
St. John’s wort (Hypericum perforatum)
↓Dolutegravir Avoid coadministration with TIVICAY because there are insufficient data to make dosing recommendations.
Medications containing polyvalent cations
(e.g., Mg or Al):
Cation-containing antacidsa or laxatives
Sucralfate
Buffered medications
↓Dolutegravir Administer TIVICAY 2 hours before or 6 hours after taking medications containing polyvalent cations.
Oral calcium or iron supplements, including multivitamins containing calcium or iron a ↓Dolutegravir Administer TIVICAY 2 hours before or 6 hours after taking supplements containing calcium or iron. Alternatively, TIVICAY and supplements containing calcium or iron can be taken together with food.
Metformin ↑Metformin With concomitant use, limit the total daily dose of metformin to 1,000 mg either when starting metformin or TIVICAY. When stopping TIVICAY, the metformin dose may require an adjustment. Monitoring of blood glucose when initiating concomitant use and after withdrawal of TIVICAY is recommended.
Rifampina ↓Dolutegravir Adjust dose of TIVICAY to 50 mg twice daily for treatment-naïve and treatment-experienced, INSTI-naïve adult patients. In pediatric patients, increase the weight-based dose to twice daily (Table 2). Use alternatives to rifampin where possible for INSTI-experienced patients with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance.b


Table name:
Bleeding times
Clinical Impact: Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention: This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact: The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention: Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact: Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention: This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including: antacids, sucralfate, multivitamins Decreased moxifloxacin hydrochloride absorption. Take moxifloxacin hydrochloride tablets at least 4 hours before or 8 hours after these products. (2.2, 7.1, 12.3)
Warfarin Anticoagulant effect enhanced. Monitor prothrombin time/INR, and bleeding. (6, 7.2, 12.3)
Class IA and Class III antiarrhythmics: Proarrhythmic effect may be enhanced. Avoid concomitant use. (5.3, 7.4)
Antidiabetic agents Carefully monitor blood glucose. ( 5.10, 7.3)


Table name:
Table 4 Established and Other Potentially SignificantThis table is not all inclusive. Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
Concomitant Drug Class: Drug Name Effect Clinical Comment
Antiretroviral agents
Protease inhibitor:
  atazanavir
↓atazanavir concentration
↑ tenofovir concentration
Coadministration of atazanavir with ATRIPLA is not recommended. Coadministration of atazanavir with either efavirenz or tenofovir DF decreases plasma concentrations of atazanavir. The combined effect of efavirenz plus tenofovir DF on atazanavir plasma concentrations is not known. Also, atazanavir has been shown to increase tenofovir concentrations. There are insufficient data to support dosing recommendations for atazanavir or atazanavir/ritonavir in combination with ATRIPLA.
Protease inhibitor:
  fosamprenavir calcium
↓ amprenavir concentration Fosamprenavir (unboosted): Appropriate doses of fosamprenavir and ATRIPLA with respect to safety and efficacy have not been established.

Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when ATRIPLA is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when ATRIPLA is administered with fosamprenavir plus ritonavir twice daily.
Protease inhibitor:
  indinavir
↓ indinavir concentration The optimal dose of indinavir, when given in combination with efavirenz, is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to efavirenz.
Protease inhibitor:
  lopinavir/ritonavir
↓ lopinavir concentration
↑ tenofovir concentration
A dose increase of lopinavir/ritonavir to 600/150 mg (3 tablets) twice daily may be considered when used in combination with efavirenz in treatment-experienced patients where decreased susceptibility to lopinavir is clinically suspected (by treatment history or laboratory evidence). Patients should be monitored for tenofovir-associated adverse reactions. ATRIPLA should be discontinued in patients who develop tenofovir-associated adverse reactions.
Protease inhibitor:
  ritonavir
↑ ritonavir concentration
↑ efavirenz concentration
When ritonavir 500 mg every 12 hours was coadministered with efavirenz 600 mg once daily, the combination was associated with a higher frequency of adverse clinical experiences (e.g., dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when ATRIPLA is used in combination with ritonavir.
Protease inhibitor:
  saquinavir
↓ saquinavir concentration Should not be used as sole protease inhibitor in combination with ATRIPLA.
CCR5 co-receptor antagonist:
  maraviroc
↓ maraviroc concentration Efavirenz decreases plasma concentrations of maraviroc. Refer to the full prescribing information for maraviroc for guidance on coadministration with ATRIPLA.
NRTI:
  didanosine
↑ didanosine concentration Higher didanosine concentrations could potentiate didanosine-associated adverse reactions, including pancreatitis and neuropathy. In patients weighing >60 kg, the didanosine dose should be reduced to 250 mg if coadministered with ATRIPLA. Data are not available to recommend a dose adjustment of didanosine for patients weighing <60 kg. Coadministration of ATRIPLA and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse reactions. For additional information, please consult the Videx / Videx EC (didanosine) prescribing information.
Other agents
Anticoagulant:
  warfarin
↑ or ↓ warfarin concentration Plasma concentrations and effects potentially increased or decreased by efavirenz.
Anticonvulsants:
  carbamazepine
↓ carbamazepine concentration
↓ efavirenz concentration
There are insufficient data to make a dose recommendation for ATRIPLA. Alternative anticonvulsant treatment should be used.
  phenytoin
  phenobarbital
↓ anticonvulsant concentration
↓ efavirenz concentration
Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted.
Antidepressants:
  bupropion
↓ buproprion concentration The effect of efavirenz on bupropion exposure is thought to be due to the induction of bupropion metabolism. Increases in bupropion dosage should be guided by clinical response, but the maximum recommended dose of bupropion should not be exceeded.
  sertraline ↓ sertraline concentration Increases in sertraline dose should be guided by clinical response.
Antifungals:
  itraconazole
↓ itraconazole concentration
↓ hydroxy-itraconazole concentration
Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered.
  ketoconazole ↓ ketoconazole concentration Drug interaction trials with ATRIPLA and ketoconazole have not been conducted. Efavirenz has the potential to decrease plasma concentrations of ketoconazole.
  posaconazole ↓ posaconazole concentration Avoid concomitant use unless the benefit outweighs the risks.
Anti-infective:
  clarithromycin
↓ clarithromycin concentration
↑ 14-OH metabolite concentration
Clinical significance unknown. In uninfected volunteers, 46% developed rash while receiving efavirenz and clarithromycin. No dose adjustment of ATRIPLA is recommended when given with clarithromycin. Alternatives to clarithromycin, such as azithromycin, should be considered. Other macrolide antibiotics, such as erythromycin, have not been studied in combination with ATRIPLA.
Antimycobacterial:
  rifabutin
↓ rifabutin concentration Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week.
Antimycobacterial:
  rifampin
↓ efavirenz concentration If ATRIPLA is coadministered with rifampin to patients weighing 50 kg or more, an additional 200 mg/day of efavirenz is recommended.
Calcium channel blockers:
  diltiazem
↓ diltiazem concentration
↓ desacetyl diltiazem concentration
↓ N-monodes-methyl diltiazem concentration
Diltiazem dose adjustments should be guided by clinical response (refer to the full prescribing information for diltiazem). No dose adjustment of ATRIPLA is necessary when administered with diltiazem.
  Others (e.g.,
  felodipine, nicardipine,
  nifedipine, verapamil)
↓ calcium channel blocker No data are available on the potential interactions of efavirenz with other calcium channel blockers that are substrates of CYP3A. The potential exists for reduction in plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response (refer to the full prescribing information for the calcium channel blocker).
HMG-CoA reductase inhibitors:
  atorvastatin
  pravastatin
  simvastatin
↓ atorvastatin concentration
↓ pravastatin concentration
↓ simvastatin concentration
Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased with efavirenz. Consult the full prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose.
Hormonal contraceptives:
Oral:
  ethinyl
  estradiol/norgestimate
↓ active metabolites of norgestimate A reliable method of barrier contraception must be used in addition to hormonal contraceptives. Efavirenz had no effect on ethinyl estradiol concentrations, but progestin levels (norelgestromin and levonorgestrel) were markedly decreased. No effect of ethinyl estradiol/norgestimate on efavirenz plasma concentrations was observed.
Implant:
  etonogestrel
↓ etonogestrel A reliable method of barrier contraception must be used in addition to hormonal contraceptives. The interaction between etonogestrel and efavirenz has not been studied. Decreased exposure of etonogestrel may be expected. There have been postmarketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients.
Immunosuppressants:
  cyclosporine,
  tacrolimus, sirolimus,
  and others
  metabolized by
  CYP3A
↓ immuno-suppressant Decreased exposure of the immunosuppressant may be expected due to CYP3A induction by efavirenz. These immunosuppressants are not anticipated to affect exposure of efavirenz. Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with ATRIPLA.
Narcotic analgesic:
  methadone
↓ methadone concentration Coadministration of efavirenz in HIV-1 infected individuals with a history of injection drug use resulted in decreased plasma levels of methadone and signs of opiate withdrawal. Methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms. Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms.


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T 4 and T 3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT 4. Continued administration results in a decrease in serum T 4 and normal FT 4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T 4 and T 3 to TBG and transthyretin. An initial increase in serum FT 4, is followed by return of FT 4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T 4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T 4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T 4 to T 3, leading to decreased T 3 levels. However, serum T 4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T 3 and T 4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T 3 concentrations by 30% with minimal change in serum T 4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T 3 and T 4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 2. Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T4 and T3 serum transport - but FT4 concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors
(SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Drug/Drug Class (Mechanism of Interaction by Voriconazole) Drug Plasma Exposure (Cmax and AUCτ) Recommendations for Drug Dosage Adjustment/Comments
Sirolimus* (CYP3A4 Inhibition) Significantly Increased Contraindicated
Rifabutin* (CYP3A4 Inhibition) Significantly Increased Contraindicated
Efavirenz (400 mg q24h)** (CYP3A4 Inhibition)

Efavirenz (300 mg q24h)**
(CYP3A4 Inhibition)
Significantly Increased



Slight Increase in AUCτ
Contraindicated



When voriconazole is coadministered
with efavirenz, voriconazole oral
maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)** (CYP3A4 Inhibition)
Low-dose Ritonavir (100 mg q12h)**
No Significant Effect of Voriconazole on Ritonavir Cmax or AUCτ
Slight Decrease in Ritonavir Cmax and AUCτ
Contraindicated because of significant reduction of voriconazole Cmax and
AUCτ
Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole Cmax and AUCτ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids (CYP450 Inhibition) Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Contraindicated
Cyclosporine* (CYP3A4 Inhibition) AUCτ Significantly Increased; No Significant Effect on Cmax When initiating therapy with voriconazole in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When voriconazole is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary
Methadone*** (CYP3A4 Inhibition) Increased Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl (CYP3A4 Inhibition) Increased Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7)].
Alfentanil (CYP3A4 Inhibition) Significantly Increased Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with voriconazole. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [see Drug Interactions (7)].
Oxycodone (CYP3A4 Inhibition) Significantly Increased Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7)].
NSAIDs**** including ibuprofen and diclofenac (CYP2C9 Inhibition) Increased Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed [see Drug Interactions (7)].
Tacrolimus* (CYP3A4 Inhibition) Significantly Increased When initiating therapy with voriconazole in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazole is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin* (CYP2C9 Inhibition) Significantly Increased Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)** Increased Monitoring for adverse events related to oral contraceptives is recommended during coadministration.
Warfarin* (CYP2C9 Inhibition) Prothrombin Time Significantly Increased Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed.
Omeprazole* (CYP2C19/3A4 Inhibition) Significantly Increased When initiating therapy with voriconazole in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors (CYP3A4 Inhibition) In Vivo Studies Showed No Significant Effects on Indinavir Exposure

In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)
No dosage adjustment for indinavir when coadministered with voriconazole

Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors
Other NNRTIs***** (CYP3A4 Inhibition) A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to NNRTI
Benzodiazepines (CYP3A4 Inhibition) In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.
HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition) In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition) In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition) Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased
Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Reserve azole antifungals, including voriconazole, for patients receiving a vinca alkaloid who have no alternative antifungal treatment options.
Everolimus
(CYP3A4 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Concomitant administration of voriconazole and everolimus is not recommended.


Table name:
Table 2. Drugs That May Decrease T4 Absorption (Hypothyroidism)
Potential impact: Concurrent use may reduce the efficacy of SYNTHROID by binding and delaying or preventing absorption, potentially resulting in hypothyroidism.
Drug or Drug Class Effect
Calcium Carbonate
Ferrous Sulfate
Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer SYNTHROID at least 4 hours apart from these agents.
Orlistat Monitor patients treated concomitantly with orlistat and SYNTHROID for changes in thyroid function.
Bile Acid Sequestrants
- Colesevelam
- Cholestyramine
- Colestipol
Ion Exchange Resins
- Kayexalate
- Sevelamer
Bile acid sequestrants and ion exchange resins are known to decrease levothyroxine absorption. Administer SYNTHROID at least 4 hours prior to these drugs or monitor TSH levels.
Other drugs:
Proton Pump Inhibitors
Sucralfate
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Gastric acidity is an essential requirement for adequate absorption of levothyroxine. Sucralfate, antacids and proton pump inhibitors may cause hypochlorhydria, affect intragastric pH, and reduce levothyroxine absorption. Monitor patients appropriately.


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T 4 and T 3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin/Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens/Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non-Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT 4 . Continued administration results in a decrease in serum T 4 and normal FT 4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T 4 and T 3 to TBG and transthyretin. An initial increase in serum FT 4 is followed by return of FT 4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T 4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T 4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ³ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T 4 to T 3, leading to decreased T 3 levels. However, serum T 4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T 3 and T 4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T 3 concentrations by 30% with minimal change in serum T 4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T 3 and T 4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias
and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123 I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Interacting Drug 
Interaction 
Multivalent cation-containing products including antacids, metal cations or didanosine 
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin 
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents 
Carefully monitor blood glucose (5.11, 7.3)


Table name:
Table 4 Established and Other Potentially SignificantThis table is not all inclusive. Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
Concomitant Drug Class: Drug Name Effect Clinical Comment
HIV antiviral agents
Protease inhibitor:
  atazanavir
↓atazanavir
↑ tenofovir
Coadministration of atazanavir with ATRIPLA is not recommended. Coadministration of atazanavir with either efavirenz or tenofovir DF decreases plasma concentrations of atazanavir. The combined effect of efavirenz plus tenofovir DF on atazanavir plasma concentrations is not known. Also, atazanavir has been shown to increase tenofovir concentrations. There are insufficient data to support dosing recommendations for atazanavir or atazanavir/ritonavir in combination with ATRIPLA.
Protease inhibitor:
  fosamprenavir calcium
↓ amprenavir Fosamprenavir (unboosted): Appropriate doses of fosamprenavir and ATRIPLA with respect to safety and efficacy have not been established.

Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when ATRIPLA is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when ATRIPLA is administered with fosamprenavir plus ritonavir twice daily.
Protease inhibitor:
  indinavir
↓ indinavir The optimal dose of indinavir, when given in combination with efavirenz, is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to efavirenz.
Protease inhibitor:
  lopinavir/ritonavir
↓ lopinavir
↑ tenofovir
Do not use once daily administration of lopinavir/ritonavir. Dose adjustment of lopinavir/ritonavir is recommended when coadministered with efavirenz. Refer to the full prescribing information for lopinavir/ritonavir for guidance on coadministration with efavirenz- or tenofovir-containing regimens, such as ATRIPLA. Patients should be monitored for tenofovir-associated adverse reactions.
Protease inhibitor:
  ritonavir
↑ ritonavir
↑ efavirenz
When ritonavir 500 mg every 12 hours was coadministered with efavirenz 600 mg once daily, the combination was associated with a higher frequency of adverse clinical experiences (e.g., dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when ATRIPLA is used in combination with ritonavir.
Protease inhibitor:
  saquinavir
↓ saquinavir Appropriate doses of the combination of efavirenz and saquinavir/ritonavir with respect to safety and efficacy have not been established.
CCR5 co-receptor antagonist:
  maraviroc
↓ maraviroc Efavirenz decreases plasma concentrations of maraviroc. Refer to the full prescribing information for maraviroc for guidance on coadministration with ATRIPLA.
NRTI:
  didanosine
↑ didanosine Coadministration of ATRIPLA and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse reactions including pancreatitis, lactic acidosis, and neuropathy. A dose reduction of didanosine is recommended when co-administered with tenofovir DF. For additional information on coadministration with tenofovir DF-containing products, please refer to the didanosine prescribing information.
NNRTI:
  Other NNRTIs
↑ or ↓ efavirenz and/or NNRTI Combining two NNRTIs has not been shown to be beneficial. ATRIPLA contains efavirenz and should not be coadministered with other NNRTIs.
Integrase strand transfer inhibitor:
  raltegravir
↓ raltegravir Efavirenz reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.
Hepatitis C antiviral agents
Protease inhibitor:
 boceprevir
↓ boceprevir Plasma trough concentrations of boceprevir were decreased when boceprevir was coadministered with efavirenz, which may result in loss of therapeutic effect. The combination should be avoided.
Protease inhibitor:
 telaprevir
↓ telaprevir
↓ efavirenz
Concomitant administration of telaprevir and efavirenz resulted in reduced steady-state exposures to telaprevir and efavirenz.
Other agents
Anticoagulant:
  warfarin
↑ or ↓ warfarin Plasma concentrations and effects potentially increased or decreased by efavirenz.
Anticonvulsants:
  carbamazepine
↓ carbamazepine
↓ efavirenz
There are insufficient data to make a dose recommendation for ATRIPLA. Alternative anticonvulsant treatment should be used.
  phenytoin
  phenobarbital
↓ anticonvulsant
↓ efavirenz
Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted.
Antidepressants:
  bupropion
↓ buproprion The effect of efavirenz on bupropion exposure is thought to be due to the induction of bupropion metabolism. Increases in bupropion dosage should be guided by clinical response, but the maximum recommended dose of bupropion should not be exceeded.
  sertraline ↓ sertraline Increases in sertraline dose should be guided by clinical response.
Antifungals:
  itraconazole
↓ itraconazole
↓ hydroxy-itraconazole
Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered.
  ketoconazole ↓ ketoconazole Drug interaction trials with ATRIPLA and ketoconazole have not been conducted. Efavirenz has the potential to decrease plasma concentrations of ketoconazole.
  posaconazole ↓ posaconazole Avoid concomitant use unless the benefit outweighs the risks.
Anti-infective:
  clarithromycin
↓ clarithromycin
↑ 14-OH metabolite
Clinical significance unknown. In uninfected volunteers, 46% developed rash while receiving efavirenz and clarithromycin. No dose adjustment of ATRIPLA is recommended when given with clarithromycin. Alternatives to clarithromycin, such as azithromycin, should be considered. Other macrolide antibiotics, such as erythromycin, have not been studied in combination with ATRIPLA.
Antimycobacterial:
  rifabutin
↓ rifabutin concentration Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week.
  rifampin ↓ efavirenz If ATRIPLA is coadministered with rifampin to patients weighing 50 kg or more, an additional 200 mg/day of efavirenz is recommended.
Calcium channel blockers:
  diltiazem
↓ diltiazem
↓ desacetyl diltiazem
↓ N-monodes-methyl diltiazem
Diltiazem dose adjustments should be guided by clinical response (refer to the full prescribing information for diltiazem). No dose adjustment of ATRIPLA is necessary when administered with diltiazem.
  Others (e.g.,
  felodipine, nicardipine,
  nifedipine, verapamil)
↓ calcium channel blocker No data are available on the potential interactions of efavirenz with other calcium channel blockers that are substrates of CYP3A. The potential exists for reduction in plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response (refer to the full prescribing information for the calcium channel blocker).
HMG-CoA reductase inhibitors:
  atorvastatin
  pravastatin
  simvastatin
↓ atorvastatin
↓ pravastatin
↓ simvastatin
Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased with efavirenz. Consult the full prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose.
Hormonal contraceptives:
Oral:
  ethinyl
  estradiol/norgestimate
↓ active metabolites of norgestimate A reliable method of barrier contraception must be used in addition to hormonal contraceptives. Efavirenz had no effect on ethinyl estradiol concentrations, but progestin levels (norelgestromin and levonorgestrel) were markedly decreased. No effect of ethinyl estradiol/norgestimate on efavirenz plasma concentrations was observed.
Implant:
  etonogestrel
↓ etonogestrel A reliable method of barrier contraception must be used in addition to hormonal contraceptives. The interaction between etonogestrel and efavirenz has not been studied. Decreased exposure of etonogestrel may be expected. There have been postmarketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients.
Immunosuppressants:
  cyclosporine,
  tacrolimus, sirolimus,
  and others
  metabolized by
  CYP3A
↓ immuno-suppressant Decreased exposure of the immunosuppressant may be expected due to CYP3A induction by efavirenz. These immunosuppressants are not anticipated to affect exposure of efavirenz. Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with ATRIPLA.
Narcotic analgesic:
  methadone
↓ methadone Coadministration of efavirenz in HIV-1 infected individuals with a history of injection drug use resulted in decreased plasma levels of methadone and signs of opiate withdrawal. Methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms. Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms.


Table name:
Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s) Recommendation Comments
Tizanidine Contraindicated Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)].
Theophylline Avoid Use (Plasma Exposure Likely to be Increased and Prolonged) Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions (5.6).]
Drugs Known to Prolong QT Interval Avoid Use Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.10) and Use in Specific Populations (8.5)].
Oral antidiabetic drugs Use with caution Glucose-lowering effect potentiated Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported . Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs. [see Adverse Reactions (6.1).]
Phenytoin Use with caution Altered serum levels of phenytoin (increased and decreased) To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after coadministration of ciprofloxacin with phenytoin.
Cyclosporine Use with caution (transient elevations in serum creatinine) Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs Use with caution (Increase in anticoagulant effect) The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole Use with caution Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after coadministration with ciprofloxacin [see Warnings and Precautions (5.15)].
Clozapine Use with caution Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs Use with caution Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil Use with caution 2-fold increase in exposure Monitor for sildenafil toxicity (see Pharmacokinetics -(12.3)-] .
Duloxetine Avoid Use 5-fold increase in duloxetine exposure If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx ® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products) Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2)]. Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels) Potentiation of ciprofloxacin toxicity may occur.


Table name:
Drug Interactions Associated with Increased Risk of  Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice Avoid grapefruit juice


Table name:
Table 6 Clinically Important Drug Interactions
Concomitant Drug Name or Drug Class Clinical Rationale Clinical Recommendation
Tricyclic antidepressants Increase blood pressure and may counteract clonidine’s hypotensive effects Monitor blood pressure and adjust as needed
Antihypertensive drugs Potentiate clonidine’s hypotensive effects Monitor blood pressure and adjust as needed
CNS depressants Potentiate sedating effects Avoid use
Drugs that affect sinus node function or AV node conduction (e.g., digitalis, calcium channel blockers, beta blockers) Potentiate bradycardia and risk of AV block Avoid use


Table name:
Table 4: Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table 5 for Magnitude of Interaction.
Drug Name Effect on Concentration of Nevirapine or Concomitant Drug Clinical Comment
HIV Antiviral Agents: Protease Inhibitors (PIs)
Atazanavir/RitonavirThe interaction between immediate-release nevirapine and the drug was evaluated in a clinical study. The results of drug interaction studies with immediate-release nevirapine are expected to also apply to nevirapine extended-release tablets. ↓ Atazanavir
↑ Nevirapine
Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures.
Fosamprenavir ↓ Amprenavir
↑ Nevirapine
Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.
Fosamprenavir/Ritonavir ↓ Amprenavir
↑ Nevirapine
No dosing adjustments are required when nevirapine is co-administered with 700 mg/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied.
Indinavir ↓ Indinavir The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established.
Lopinavir/Ritonavir ↓ Lopinavir Dosing in adult patients: A dose adjustment of lopinavir/ritonavir to 500 mg/125 mg tablets twice daily or 533 mg/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. Dosing in pediatric patients: Please refer to the Kaletra® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.
Nelfinavir ↓ Nelfinavir M8 Metabolite
↓ Nelfinavir Cmin
The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established.
Saquinavir/Ritonavir The interaction between nevirapine and saquinavir/ritonavir has not been evaluated The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz ↓ Efavirenz The appropriate doses of these combinations with respect to safety and efficacy have not been established.
Delavirdine
Etravirine
Rilpivirine
Plasma concentrations may be altered. Nevirapine should not be co-administered with another NNRTI as this combination has not been shown to be beneficial.
Hepatitis C Antiviral Agents
Boceprevir Plasma concentrations of boceprevir may be decreased due to induction of CYP3A4/5 by nevirapine. Nevirapine and boceprevir should not be co-administered because decreases in boceprevir plasma concentrations may result in a reduction in efficacy.
Telaprevir Plasma concentrations of telaprevir may be decreased due to induction of CYP3A4 by nevirapine and plasma concentrations of nevirapine may be increased due to inhibition of CYP3A4 by telaprevir. Nevirapine and telaprevir should not be co-administered because changes in plasma concentrations of nevirapine, telaprevir, or both may result in a reduction in telaprevir efficacy or an increase in nevirapine-associated adverse events.
Other Agents
Analgesics:
Methadone
 
↓ Methadone
 
Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Antiarrhythmics:
Amiodarone, disopyramide, lidocaine
Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Antibiotics:
Clarithromycin
 
↓ Clarithromycin
↑ 14-OH clarithromycin
 
Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.
 
Rifabutin ↑ Rifabutin Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.
 
Rifampin ↓ Nevirapine Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Anticonvulsants:
Carbamazepine, clonazepam, ethosuximide
Plasma concentrations of nevirapine and the anticonvulsant may be decreased. Use with caution and monitor virologic response and levels of anticonvulsants.
Antifungals:
Fluconazole
 
↑ Nevirapine
 
Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events.
 
Ketoconazole ↓ Ketoconazole Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.
 
Itraconazole ↓ Itraconazole Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug.
Antithrombotics:
Warfarin
 
Plasma concentrations may be increased.
 
Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.
Calcium channel blockers:
Diltiazem, nifedipine, verapamil
 
Plasma concentrations may be decreased.
 
Appropriate doses for these combinations have not been established.
Cancer chemotherapy:
Cyclophosphamide
 
Plasma concentrations may be decreased.
 
Appropriate doses for this combination have not been established.
Ergot alkaloids:
Ergotamine
 
Plasma concentrations may be decreased.
 
Appropriate doses for this combination have not been established.
Immunosuppressants:
Cyclosporine, tacrolimus, sirolimus
 
Plasma concentrations may be decreased.
 
Appropriate doses for these combinations have not been established.
Motility agents:
Cisapride
 
Plasma concentrations may be decreased.
 
Appropriate doses for this combination have not been established.
Opiate agonists:
Fentanyl
 
Plasma concentrations may be decreased.
 
Appropriate doses for this combination have not been established.
Oral contraceptives:
Ethinyl estradiol and Norethindrone
 
↓ Ethinyl estradiol
↓ Norethindrone
 
Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended.


Table name:
Table 2: Clinically Relevant Interactions Affecting Drugs Co-Administered with Rabeprazole Sodium Delayed-Release Tablets
Antiretrovirals 
Clinical Impact: 

The effect of PPI on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. 

•  Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir, and nelfinavir) when used concomitantly with rabeprazole may reduce antiviral effect and promote the
 development of drug resistance. 

•  Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with rabeprazole may increase toxicity.

•  There are other antiretroviral drugs which do not result in clinically relevant interactions with rabeprazole. 
Rilpivirine-containing products: Concomitant use with rabeprazole sodium delayed-release tablets are contraindicated [see CONTRAINDICATIONS (4)]. See prescribing information.
Atazanavir: See prescribing information for atazanavir for dosing information. 
Intervention: 
Nelfinavir: Avoid concomitant use with rabeprazole sodium delayed-release tablets. See prescribing information for nelfinavir. 
Saquinavir: See the prescribing information for saquinavir and monitor for potential saquinavir toxicities. 
Other antiretrovirals: See prescribing information. 
Warfarin 
Clinical Impact: 

Increased INR and prothrombin time in patients receiving PPIs, including rabeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal  bleeding and even death [see WARNINGS AND PRECAUTIONS (5.2)].
Intervention: 
Monitor INR and prothrombin time. Dose adjustment of warfarin may be needed to maintain target INR range. See prescribing information for warfarin. 
Methotrexate 
Clinical Impact: 

Concomitant use of rabeprazole with methotrexate (primarily at high dose) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate,  possibly leading to methotrexate toxicities. No formal drug interaction studies of methotrexate with PPIs have been conducted [see WARNINGS AND PRECAUTIONS (5.9)].
Intervention: 

A temporary withdrawal of rabeprazole sodium delayed-release tablets may be considered in some patients receiving high dose methotrexate administration. 
Digoxin 
Clinical Impact: 
Potential for increased exposure of digoxin [see CLINICAL PHARMACOLOGY (12.3)].
Intervention: 
Monitor digoxin concentrations. Dose adjustment of digoxin may be needed to maintain therapeutic drug concentrations. See prescribing information for digoxin. 
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole, itraconazole) 
Clinical Impact: 
Rabeprazole can reduce the absorption of drugs due to its effect on reducing intragastric acidity. 
Intervention: 
Mycophenolate mofetil (MMF): Co-administration of PPIs in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, 
mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in 
transplant patients receiving PPIs and MMF. Use rabeprazole sodium delayed-release tablets with caution in transplant patients receiving MMF. 

See the prescribing information for other drugs dependent on gastric pH for absorption. 
Combination Therapy with Clarithromycin and Amoxicillin 
Clinical Impact: 
Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated.

Amoxicillin also has drug interactions. 
Intervention: 
See CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS in prescribing information for clarithromycin. See DRUG INTERACTIONS in prescribing information for amoxicillin.


Table name:
a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
b = Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated
AED Co-administered 
AED Concentration
Topiramate Concentration
Phenytoin 
NC or 25% increasea
48% decrease
Carbamazepine (CBZ)
NC 
40% decrease
CBZ epoxideb
NC
NE
Valproic acid 
11% decrease
14% decrease
Phenobarbital
NC
NE
Primidone 
NC
NE
Lamotrigine 
NC at TPM doses up to 400 mg/day
13% decrease


Table name:
Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) VIAGRA 25 mg
Supine 7.4 (-0.9, 15.7)
Standing 6.0 (-0.8, 12.8)


Table name:
Table 1: Clinically Significant Drug Interactions with DILAUDID
Benzodiazepines and other Central Nervous System (CNS) Depressants
Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.5)].
Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome
Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue DILAUDID Oral Solution or DILAUDID Tablets if serotonin syndrome is suspected.
Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.3)].
If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
Intervention: The use of DILAUDID Oral Solution or DILAUDID Tablets is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples: phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact: May reduce the analgesic effect of DILAUDID Oral Solution or DILAUDID Tablets and/or precipitate withdrawal symptoms.
Intervention: Avoid concomitant use.
Examples: butorphanol, nalbuphine, pentazocine, buprenorphine,
Muscle Relaxants
Clinical Impact: Hydromorphone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of DILAUDID Oral Solution or DILAUDID Tablets and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when DILAUDID Oral Solution or DILAUDID Tablets is used concomitantly with anticholinergic drugs.


Table name:
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)   Avoid atorvastatin  
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) Do not exceed 40 mg atorvastatin daily


Table name:
Figure 2: Effect of venlafaxine on the pharmacokinetics interacting drugs and their active metabolites.


Table name:
Interacting  Drug 
Interaction
Multivalent cation-containing
products including antacids,
metal cations or didanosine
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. ( 2.4, 7.1)
Warfarin
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( 7.2)
Antidibetic agents
Carefully monitor blood glucose ( 5.11, 7.3)


Table name:
Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.*
*Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol,  systemic and inhaled felodipinefinasteride nizatidinenorfloxacin
amoxicillin hydrocortisone ofloxacin
ampicillin,   with or without sulbactam isoflurane isoniazid omeprazole prednisone, prednisolone
atenolol isradipine ranitidine
azithromycin influenza vaccine rifabutin
caffeine,   dietary ingestion ketoconazo lelomefloxacin roxithromycin sorbitol
cefaclor mebendazole         (purgative doses do not
co-trimoxazole  (trimethoprim and sulfamethoxazole) medroxyprogesteronemethylprednisolone    inhibit theophylline   absorption)
diltiazem metronidazole sucralfate
dirithromycin metoprolol terbutaline, systemic
enflurane nadolol terfenadine
famotidine nifedipine tetracycline
tocainide


Table name:
Table 18. Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia Coadministered Drug Dosing Schedule Effect on Active
Coadministered Drug Dosing Schedule Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (RatioChange relative to reference) Risperidone Dose Recommendation
Coadministered Drug Risperidone AUC Cmax
Enzyme (CYP2D6) Inhibitors
Fluoxetine 20 mg/day 2 or 3 mg twice daily 1.4 1.5 Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine 10 mg/day 4 mg/day 1.3 - Re-evaluate dosing. Do not exceed 8 mg/day
20 mg/day 4 mg/day 1.6 -
40 mg/day 4 mg/day 1.8 -
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine 573 ± 168 mg/day 3 mg twice daily 0.51 0.55 Titrate dose upwards. Do not exceed twice the patient's usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine 150 mg twice daily 1 mg single dose 1.2 1.4 Dose adjustment not needed
Cimetidine 400 mg twice daily 1 mg single dose 1.1 1.3 Dose adjustment not needed
Erythromycin 500 mg four times daily 1 mg single dose 1.1 0.94 Dose adjustment not needed
Other Drugs
Amitriptyline 50 mg twice daily 3 mg twice daily 1.2 1.1 Dose adjustment not needed


Table name:
Concomitant Drug
Effect on  Concentration of Lamotrigine or Concomitant Drug
Clinical Comment
Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel

↓ lamotrigine
 
 
 ↓ levonorgestrel

Decreased lamotrigine levels approximately 50%.
 
Decrease in levonorgestrel component by 19%.

Carbamazepine (CBZ)
and CBZ epoxide
↓ lamotrigine

  
 
 ? CBZ epoxide

Addition of carbamazepine decreases lamotrigine concentration approximately 40% 
 
May increase CBZ epoxide levels
Phenobarbital/Primidone
↓ lamotrigine
Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)
↓ lamotrigine
Decreased lamotrigine concentration approximately 40%.
Rifampin
↓ lamotrigine
Decreased lamotrigine AUC approximately 40%.
Valproate

↑ lamotrigine
 
 
 ? valproate

Increased lamotrigine concentrations slightly more than 2-fold.
 
Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
Concomitant Drug Class:
Drug Name
Effect on Concentration Clinical Comment
HIV-1 Antiviral Agents
Non-nucleoside reverse transcriptase inhibitor: Etravirinea ↓Dolutegravir Use of TRIUMEQ with etravirine without coadministration of atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir is not recommended.
Non-nucleoside reverse transcriptase inhibitor: Efavirenza ↓Dolutegravir Adjust dolutegravir dose to 50 mg twice daily. An additional 50-mg dose of dolutegravir should be taken, separated by 12 hours from TRIUMEQ.
Non-nucleoside reverse transcriptase inhibitor: Nevirapine ↓Dolutegravir Avoid coadministration with TRIUMEQ because there are insufficient data to make dosing recommendations.
Protease inhibitor: Fosamprenavir/ritonavira
Tipranavir/ritonavira
↓Dolutegravir Adjust dolutegravir dose to 50 mg twice daily. An additional dolutegravir 50-mg dose should be taken, separated by 12 hours from TRIUMEQ.
Other Agents
Carbamazepinea ↓Dolutegravir Adjust dolutegravir dose to 50 mg twice daily. An additional dolutegravir 50-mg dose should be taken, separated by 12 hours from TRIUMEQ.
Oxcarbazepine
Phenytoin
Phenobarbital
St. John’s wort (Hypericum perforatum)
↓Dolutegravir Avoid coadministration with TRIUMEQ because there are insufficient data to make dosing recommendations.
Medications containing polyvalent cations
(e.g., Mg or Al):
Cation-containing antacidsa or laxatives
Sucralfate
Buffered medications
↓Dolutegravir Administer TRIUMEQ 2 hours before or 6 hours after taking medications containing polyvalent cations.
Oral calcium and iron supplements, including multivitamins containing calcium or irona ↓Dolutegravir Administer TRIUMEQ 2 hours before or 6 hours after taking supplements containing calcium or iron. Alternatively, TRIUMEQ and supplements containing calcium or iron can be taken together with food.
Metformina ↑Metformin With concomitant use, limit the total daily dose of metformin to 1,000 mg either when starting metformin or TRIUMEQ. When stopping TRIUMEQ, the metformin dose may require an adjustment. Monitoring of blood glucose when initiating concomitant use and after withdrawal of TRIUMEQ is recommended.
Rifampina ↓Dolutegravir Adjust dolutegravir dose to 50 mg twice daily. An additional 50-mg dose of dolutegravir should be taken, separated by 12 hours from TRIUMEQ.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 4, 5.1, 7.1, 7.2, 7.3, 7.6, 7.8, 12.3)
Interacting Agents Prescribing Recommendations
Strong CYP3A4 Inhibitors, (e.g., itraconazole, ketoconazole,
posaconazole, erythromycin,
clarithromycin, telithromycin,
HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol
Contraindicated with VYTORIN
Verapamil, diltiazem Do not exceed 10/10 mg VYTORIN daily
Amiodarone, amlodipine, ranolazine Do not exceed 10/20 mg VYTORIN daily
Grapefruit juice Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Classes of Drugs
Adrenal Cortical Steroid
Inhibitors
Antacids
Antianxiety Agents
Antiarrhythmics†
Antibiotics†
Anticonvulsants†
Antidepressants†
Antihistamines
Antineoplastics†
Antipsychotic Medications
Antithyroid Drugs†
Barbiturates
Diuretics†
Enteral Nutritional
Supplements
Fungal Medications, Systemic†
Gastric Acidity and Peptic
Ulcer Agents†
Hypnotics†
Hypolipidemics†
Bile Acid-Binding Resins†
HMG-CoA Reductase Inhibitors†
Immunosuppressives
Oral Contraceptives, Estrogen
Containing
Selective Estrogen Receptor
Modulators
Steroids, Adrenocortical†
Tuberculosis Agents†
Vitamins†


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine Do not exceed 10 mg atorvastatin daily
Clarithromycin, itraconazole, HIV protease inhibitors (ritonavir plus saquinavir or lopinavir plus ritonavir) Caution when exceeding doses > 20 mg atorvastatin daily. The lowest dose necessary should be used.


Table name: ContraindicatedAvoid UseUse with cautionUse with cautionUse with caution
Table 8: Drugs That are Affected by and Affecting CIPRO IV
Drugs That are Affected by CIPRO IV
Drug(s) Recommendation Comments
Tizanidine
 
Concomitant administration of tizanidine and CIPRO IV is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)]
Theophylline Avoid Use (Plasma Exposure Likely to be Increased and Prolonged) Concurrent administration of CIPRO IV with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [eee Warnings and Precautions (5.9)].
Drugs Known to Prolong QT Interval
 
CIPRO IV may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.11) and Use in Specific Populations (8.5)].
Oral antidiabetic drugs Use with caution Glucose-lowering effect potentiated Hypoglycemia sometimes severe has been reported when CIPRO IV and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs [see Adverse Reactions (6.1)].
Phenytoin Use with caution Altered serum levels of phenytoin (increased and decreased) To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon CIPRO IV discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of CIPRO IV with phenytoin.
Cyclosporine Use with caution (transient elevations in serum creatinine) Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs Use with caution (Increase in anticoagulant effect) The risk may vary with the underlying infection, age and general status of the patient so that the contribution of CIPRO IV to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of CIPRO IV with an oral anti-coagulant (for example, warfarin).
Methotrexate Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant CIPRO IV therapy is indicated.
Ropinirole
 
Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with CIPRO IV [see Warnings and Precautions (5.15)].
Clozapine
 
Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with CIPRO IV are advised.
NSAIDs
 
Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil Use with caution Two-fold increase in exposure Monitor for sildenafil toxicity [see Clinical Pharmacology (12.3)].
Duloxetine Avoid Use Five-fold increase in duloxetine exposure If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life CIPRO IV inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of CIPRO
Probenecid Use with caution (interferes with renal tubular secretion of CIPRO and increases CIPRO serum levels) Potentiation of CIPRO IV toxicity may occur.


Table name:
Interacting  Drug
Interaction
Multivalent cation-containing products including 
antacids, metal cations or didanosine
Absorption of levofloxacin is decreased when  the tablet is taken within 2 hours of these products. (2.4, 7.1)
Warfarin
Effect may be enhanced. Monitor prothrombin time,  INR, watch for bleeding (7.2)
Antidiabetic agents
Carefully monitor blood glucose (5.12, 7.3)


Table name:
TABLE 2. Mean (± S.D.) Pharmacokinetic Parameters for Estradiol, Estrone, and Equilin Following Coadministration of Conjugated Estrogens 0.625 mg and Progesterone Capsules 200 mg for 12 Days to Postmenopausal Women
a Total estrogens is the sum of conjugated and unconjugated estrogen.
  Conjugated Estrogens Conjugated Estrogens plus Progesterone Capsules
Drug Cmax
(ng/mL)
Tmax
(hr)
AUC(0-24h)
(ng × h/mL)
Cmax
(ng/mL)
Tmax
(hr)
AUC(0-24h)
(ng × h/mL)
Estradiol 0.037
± 0.048
12.7
± 9.1
0.676
± 0.737
0.030
± 0.032
17.32
± 1.21
0.561
± 0.572
Estrone
Total a
3.68
± 1.55
10.6
± 6.8
61.3
± 26.36
4.93
± 2.07
7.5
± 3.8
85.9
± 41.2
Equilin
Total a
2.27
± 0.95
6.0
± 4.0
28.8
± 13.0
3.22
± 1.13
5.3
± 2.6
38.1
± 20.2


Table name:
Interacting Drug Interaction
Drugs known to prolong QT interval (e.g., Class IA and Class III antiarrhythmic agents). QUALAQUIN prolongs QT interval, ECG abnormalities including QT prolongation and Torsades de Pointes. Avoid concomitant use (5.3).
Other antimalarials (e.g., halofantrine, mefloquine). ECG abnormalities including QT prolongation. Avoid concomitant use (5.3, 7.2).
CYP3A4 inducers or inhibitors Alteration in plasma quinine concentration. Monitor for lack of efficacy or increased adverse events of quinine (7.1).
CYP3A4 and CYP2D6 substrates Quinine is an inhibitor of CYP3A4 and CYP2D6. Monitor for lack of efficacy or increased adverse events of the co-administered drug (7.2).
Digoxin Increased digoxin plasma concentration (5.8, 7.1).


Table name:
  Concomitant Drug Name or Drug Class   Clinical Rationale   Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)]. With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin) The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see  CLINICAL PHARMACOLOGY (12.3)].

With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
 Antihypertensive Drugs Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.7)].

 Benzodiazepines (e.g., lorazepam) The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.7)] Monitor sedation and blood pressure. Adjust dose accordingly.


Table name:
Concomitant Drug Name or Drug Class Clinical Rationale Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) The concomitant use of aripiprazole with strong CYP3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)]. With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin) The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)]. With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Antihypertensive Drugs Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.8)].
Benzodiazepines (e.g., lorazepam) The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.8)]. Monitor sedation and blood pressure. Adjust dose accordingly.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir ) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
CYP2C19 or CYP3A4 Inducers 
Clinical Impact:  Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology (12.3) ]. 
Intervention:  S t . John’s Wort, rifampin: Avoid concomitant use with Omeprazole Delayed-Release Capsules [ see W arnings and  P recautions (5.9)] . Ritonavir-containing products:  see prescribing information for specific drugs. 
CYP2C19 or CYP3A4 Inhibitors 
Clinical Impact:  Increased exposure of omeprazole [see C l i n i cal Pharmacology (12.3)]. 
Intervention:  V oriconazole: Dose adjustment of Omeprazole Delayed-Release Capsules is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered. See prescribing information for voriconazole. 


Table name:

albuterol, systemic and inhaled

mebendazole

amoxicillin

medroxyprogesterone

ampicillin, with or without

methylprednisolone

sulbactam

metronidazole

atenolol

metoprolol

azithromycin

nadolol

caffeine, dietary ingestion

nifedipine

cefaclor

nizatidine

co-trimoxazole (trimethoprim and

sulfamethoxazole)

norfloxacin

ofloxacin

diltiazem

omeprazole

dirithromycin

prednisone, prednisolone

enflurane

ranitidine

famotidine

rifabutin

felodipine

roxithromycin

finasteride

Sorbitol (purgative doses do not inhibit

hydrocortisone

theophylline absorption)

isoflurane

sucralfate

isoniazid

terbutaline, systemic

isradipine

terfenadine

influenza vaccine

tetracycline

ketoconazole

tocainide

lomefloxacin

 


Table name:
Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s) Recommendation Comments
Tizanidine Contraindicated Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)].
Theophylline Avoid Use (Plasma Exposure Likely to be Increased and Prolonged) Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions (5.6).]
Drugs Known to Prolong QT Interval Avoid Use Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.10) and Use in Specific Populations (8.5)].
Oral antidiabetic drugs Use with caution Glucose-lowering effect potentiated Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported . Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs. [see Adverse Reactions (6.1).]
Phenytoin Use with caution Altered serum levels of phenytoin (increased and decreased) To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after coadministration of ciprofloxacin with phenytoin.
Cyclosporine Use with caution (transient elevations in serum creatinine) Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs Use with caution (Increase in anticoagulant effect) The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole Use with caution Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after coadministration with ciprofloxacin [see Warnings and Precautions (5.15)].
Clozapine Use with caution Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs Use with caution Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil Use with caution 2-fold increase in exposure Monitor for sildenafil toxicity (see Pharmacokinetics -(12.3)-] .
Duloxetine Avoid Use 5-fold increase in duloxetine exposure If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx ® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products) Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2)]. Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels) Potentiation of ciprofloxacin toxicity may occur.


Table name:
Drugs That Interfere with Hemostasis
  Clinical Impact: Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of celecoxib capsules with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11) ].
Aspirin
   Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2) ]. In two studies in healthy volunteers, and in patients with osteoarthritis and established heart disease respectively, celecoxib (200-400 mg daily) has demonstrated a lack of interference with the cardioprotective antiplatelet effect of aspirin (100-325 mg).
Intervention: Concomitant use of celecoxib capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11) ]. Celecoxib capsules are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
  Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
   Intervention: During concomitant use of celecoxib capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of celecoxib capsules and ACE-inhibitors or ARBs in patients who are elderly, volume- depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6) ]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of celecoxib capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6) ].
Digoxin
Clinical Impact: The concomitant use of celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of celecoxib capsules and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of celecoxib capsules and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Celecoxib capsules have no effect on methotrexate pharmacokinetics.
Intervention: During concomitant use of celecoxib capsules and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of celecoxib capsules and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of celecoxib capsules and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2) ].
Intervention: The concomitant use of celecoxib with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of celecoxib capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of celecoxib capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.
NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.
In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
CYP2C9 Inhibitors or inducers
Clinical Impact: Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Co­-administration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of celecoxib.
Intervention Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers [see Clinical Pharmacology (12.3) ].
CYP2D6 substrates
Clinical Impact: In vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6 (e.g. atomoxetine), and celecoxib may enhance the exposure and toxicity of these drugs.
Intervention Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2D6 substrates [see Clinical Pharmacology (12.3) ].
Corticosteroids
Clinical Impact: Concomitant use of corticosteroids with celecoxib capsules may increase the risk of GI ulceration or bleeding.
Intervention Monitor patients with concomitant use of celecoxib capsules with corticosteroids for signs of bleeding [see Warnings and Precautions (5.2)].


Table name:
DRUG DISCRIPTION OF INTERACTION
Corticosteroids Decreases plasma salicylate level; tapering doses of steroids may promote salicylism.
Acidifying agents Increases plasma salicylate levels.
Alkcanizing agents Decreased plasma salicylate levels.


Table name:
Drugs That Interfere with Hemostasis
Clinical Impact: Indomethacin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of indomethacin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of indomethacin with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ see Warnings and Precautions ( 5.11 )].
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ see Warnings and Precautions ( 5.2 ) ].
Intervention: Concomitant use of indomethacin capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions ( 5.11 )].Indomethacin is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: During concomitant use of indomethacin capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.During concomitant use of indomethacin capsules and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ see Warnings and Precautions ( 5.6 )].When these drugs are administered concomitantly, patients should be adequately hydrated.  Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.It has been reported that the addition of triamterene to a maintenance schedule of Indomethacin resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin and triamterene should not be administered together.Both indomethacin and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently [ see Warnings and Precautions ( 5.6 )].
Intervention: Indomethacin and triamterene should not be administered together. During concomitant use of indomethacin capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects. Be aware that indomethacin and potassium-sparing diuretics may both be associated with increased serum potassium levels. [ see Warnings and Precautions ( 5.6 )].
Digoxin
Clinical Impact: The concomitant use of indomethacin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of indomethacin capsules and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of indomethacin capsules and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of indomethacin capsules and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of indomethacin capsules and cyclosporine may increase cyclosporine's nephrotoxicity.
Intervention: During concomitant use of indomethacin capsules and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ see Warnings and Precautions ( 5.2 )]. Combined use with diflunisal may be particularly hazardous because diflunisal causes significantly higher plasma levels of indomethacin [see Clinical Pharmacology ( 12.3 )].In some patients, combined use of indomethacin and diflunisal has been associated with fatal gastrointestinal hemorrhage.
Intervention: The concomitant use of indomethacin with other NSAIDs or salicylates, especially diflunisal, is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of indomethacin capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of indomethacin capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Probenecid
Clinical Impact: When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased.
Intervention: During the concomitant use of indomethacin and probenecid, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect.  When increases in the dose of indomethacin are made, they should be made carefully and in small increments.


Table name:
Table 3. Drug(s) Affecting Pharmacokinetics of CRESEMBA
a 400 mg of lopinavir in combination with 100 mg of ritonavir.
Recommendation Comments
Ketoconazole Contraindicate coadministration of all potent CYP3A4 inhibitors There is more than a 5-fold increase in exposure of isavuconazole upon coadministration with ketoconazole
[see Clinical Pharmacology (12.3)].
Lopinavir/ritonavira Caution is advised when CRESEMBA is coadministered with lopinavir/ritonavir There is a 96% increase in exposure of isavuconazole when coadministered with lopinavir/ritonavir
[see Clinical Pharmacology (12.3)].
Rifampin Contraindicate coadministration of all potent CYP3A4 inducers There is a 97% decrease in exposure of isavuconazole upon coadministration with rifampin
[see Clinical Pharmacology (12.3)].


Table name:
Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s) Recommendation Comments
Tizanidine Contraindicated Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [ see Contraindications (4.2) ] .
Theophylline Avoid Use
(Plasma Exposure Likely to be
Increased and Prolonged)
Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [ s ee Warnings and Precautions (5.9) ] .
Drugs Known to
Prolong QT Interval
Avoid Use Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.11) and Use in Specific Populations (8.5) ].
Oral antidiabetic drugs Use with caution
Glucose-lowering effect potentiated
Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were coadministered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is coadministered with oral antidiabetic drugs [ s ee Adverse Reactions (6.1) ] .
Phenytoin Use with caution
Altered serum levels of phenytoin (increased and decreased)
To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after coadministration of ciprofloxacin with phenytoin.
Cyclosporine Use with caution
(transient elevations in serum creatinine)
Monitor renal function (in particular serum creatinine) when ciprofloxacin is coadministered with cyclosporine.
Anti-coagulant drugs Use with caution
(Increase in anticoagulant effect)
The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after coadministration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate Use with caution
Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels
Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole Use with caution Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after coadministration with ciprofloxacin [see Warnings and Precautions (5.16) ].
Clozapine Use with caution Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after coadministration with ciprofloxacin are advised.
NSAIDs Use with caution Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil Use with caution
Two-fold increase in exposure
Monitor for sildenafil toxicity [ s ee   C li n ic a l
Pha r m a c o l og y   ( 1 2 .3)].
Duloxetine Avoid Use
Five-fold increase in duloxetine exposure
If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine
Derivatives
Use with caution
Reduced clearance resulting in elevated levels and prolongation of serum half-life
Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate,
Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx®
(didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)
Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration  (2.4) ]. Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid Use with caution
(interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)
Potentiation of ciprofloxacin toxicity may occur.


Table name:
Inhibitors of CYP3A4
Clinical Impact: The concomitant use of fentanyl transdermal system and CYP3A4 inhibitors can increase the plasma concentration of fentanyl, resulting in increased or prolonged opioid effects particularly when an inhibitor is added after a stable dose of fentanyl transdermal system is achieved [see Warnings and Precautions (5.5)].

After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the fentanyl transdermal system plasma concentration will decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to fentanyl.
Intervention: If concomitant use is necessary, consider dosage reduction of fentanyl transdermal system until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals.

If a CYP3A4 inhibitor is discontinued, consider increasing the fentanyl transdermal system dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
Examples Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir), grape fruit juice
CYP3A4 Inducers
Clinical Impact: The concomitant use of fentanyl transdermal system and CYP3A4 inducers can decrease the plasma concentration of fentanyl [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to fentanyl [see Warnings and Precautions (5.5)].

After stopping a CYP3A4 inducer, as the effects of the inducer decline, the fentanyl plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.
Intervention: If concomitant use is necessary, consider increasing the fentanyl transdermal system dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider fentanyl transdermal system dosage reduction and monitor for signs of respiratory depression.
Examples: Rifampin, carbamazepine, phenytoin
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.7)].
Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Warnings and Precautions 5.10].
Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue fentanyl transdermal system if serotonin syndrome is suspected.
Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome [see Warnings and Precautions (5.10)] or opioid toxicity (e.g., respiratory depression, coma).
Intervention: The use of fentanyl transdermal system is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples: phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact: May reduce the analgesic effect of fentanyl transdermal system and/or precipitate withdrawal symptoms.
Intervention: Avoid concomitant use.
Examples: butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact: Fentanyl transdermal system may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of fentanyl transdermal system and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when fentanyl transdermal system is used concomitantly with anticholinergic drugs.


Table name: Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology (12.3)]. Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see Clinical Pharmacology (12.3)]. There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole.
Table 3: Clinically Relevant Interactions Affecting Drugs Co-Administered with Omeprazole and Interaction with Diagnostics
Antiretrovirals
Clinical Impact:
The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known.
Intervention:
Rilpivirine-containing products: Concomitant use with omeprazole is contraindicated [see Contraindications (4)].
 
Atazanavir: Avoid concomitant use with omeprazole. See prescribing information for atazanavir for dosing information.
 
Nelfinavir: Avoid concomitant use with omeprazole. See prescribing information for nelfinavir.
 
Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities.
 
Other antiretrovirals: See prescribing information for specific antiretroviral drugs.
Warfarin
Clinical Impact:
Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
Intervention:
Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range.
Methotrexate
Clinical Impact:
Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions (5.11)].
Intervention:
A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate.
CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam)
Clopidogrel
Clinical Impact:
Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology (12.3)].
There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel.
Intervention:
Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy [see Warnings and Precautions (5.6)].
Citalopram
Clinical Impact:
Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology (12.3)].
Intervention:
Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.
Cilostazol
Clinical Impact:
Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology (12.3)].
Intervention:
Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.
Phenytoin
Clinical Impact:
Potential for increased exposure of phenytoin.
Intervention:
Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin.
Diazepam
Clinical Impact:
Increased exposure of diazepam [see Clinical Pharmacology (12.3)].
Intervention:
Monitor patients for increased sedation and reduce the dose of diazepam as needed.
Digoxin
Clinical Impact:
Potential for increased exposure of digoxin [see Clinical Pharmacology (12.3)].
Intervention:
Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)
Clinical Impact:
Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
Intervention:
Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF [see Clinical Pharmacology (12.3)].
 
See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact:
Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions.
Intervention:
See Contraindications, Warnings and Precautions  in prescribing information for clarithromycin.
 
See Drug Interactions in prescribing information for amoxicillin.
Tacrolimus
Clinical Impact:
Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.
Intervention:
Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact:
Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions (5.10), Clinical Pharmacology (12.2)].
Intervention:
Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
Interaction with Secretin Stimulation Test
Clinical Impact:
Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention:
Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology (12.2)].
False Positive Urine Tests for THC
Clinical Impact:
There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.
Intervention:
An alternative confirmatory method should be considered to verify positive results.
Other
Clinical Impact:
There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram).
Intervention:
Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole.


Table name:
Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme
Inhibitors
Inducers
CYP2C9 
amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast
aprepitant, bosentan, carbamazepine, phenobarbital, rifampin 
CYP1A2 
acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton
montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking 
CYP3A4 
alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton
armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide 


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.11, 7.3)


Table name:
Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug Dosing Schedule Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio Change relative to reference) Risperidone Dose Recommendation
Coadministered Drug Risperidone AUC Cmax
Enzyme (CYP2D6) Inhibitors
Fluoxetine 20 mg/day 2 or 3 mg twice daily 1.4 1.5 Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine 10 mg/day 4 mg/day 1.3 - Re-evaluate dosing. Do not exceed 8 mg/day
20 mg/day 4 mg/day 1.6 -
40 mg/day 4 mg/day 1.8 -
Enzyme (CYP3A/PgP inducers) Inducers
Carbamazepine 573 ± 168 mg/day 3 mg twice daily 0.51 0.55 Titrate dose upwards. Do not exceed twice the patient's usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine 150 mg twice daily 1 mg single dose 1.2 1.4 Dose adjustment not needed
Cimetidine 400 mg twice daily 1 mg single dose 1.1 1.3 Dose adjustment not needed
Erythromycin 500 mg four times daily 1 mg single dose 1.1 0.94 Dose adjustment not needed
Other Drugs
Amitriptyline 50 mg twice daily 3 mg twice daily 1.2 1.1 Dose adjustment not needed


Table name:
Table 7 Summary of AED Interactions with Oxcarbazepine Tablets, USP
AED Coadministered Dose of AED
(mg/day)
Oxcarbazepine Tablets Dose
(mg/day)
Influence of Oxcarbazepine Tablets on AED Concentration
(Mean Change, 90% Confidence Interval)
Influence of AED on MHD Concentration
(Mean Change, 90% Confidence Interval)
Carbamazepine 400-2000 900 ncnc denotes a mean change of less than 10% 40% decrease
[CI: 17% decrease, 57% decrease]
Phenobarbital 100-150 600-1800 14% increase
[CI: 2% increase, 24% increase]
25% decrease
[CI: 12% decrease, 51% decrease]
Phenytoin 250-500 600-1800
>1200-2400
nc , Pediatrics
up to 40% increaseMean increase in adults at high oxcarbazepine tablets, USP doses
[CI: 12% increase, 60% increase]
30% decrease
[CI: 3% decrease, 48% decrease]
Valproic acid 400-2800 600-1800 nc 18% decrease
[CI: 13% decrease, 40% decrease]


Table name:
AED  Co - administered
AED  Concentration
Topiramate  Concentration
Phenytoin
NCor25%increase a
48%decrease
Carbamazepine(CBZ)
NC
40%decrease
CBZepoxide b
NC 
            NE
Valproic acid
11%decrease
14%decrease
Phenobarbital
NC
            NE
Primidone
NC
           NE
Lamotrigine
NCatTPM dosesupto400  mg/day 
         13%decrease


Table name:
 Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
 Interacting Agents  Prescribing Recommendations
 Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)  Avoid atorvastatin
 HIV protease inhibitor (lopinavir plus ritonavir)  Use with caution and lowest dose necessary
 Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)  Do not exceed 20 mg atorvastatin daily
 HIV protease inhibitor (nelfinavir)
Hepatitis C Protease inhibitor (boceprevir)
 Do not exceed 40 mg atorvastatin daily


Table name:
Rifabutin Interaction StudiesND - No data
AUC - Area under the Concentration vs. Time Curve
Cmax - Maximum serum concentration
Coadministered Drugs Effect on Rifabutin Effect on Coadministered Drug Comments
ANTIVIRALS
Amprenavir 2.9-fold ↑ AUC, 2.2-fold ↑ Cmax No significant change in kinetics. A 50% reduction in the rifabutin dose is recommended when combined with amprenavir. Increased monitoring for adverse reactions is warranted.
Delavirdine ND Oral clearance ↑ 5-fold resulting in significantly lower mean trough plasma concentrations (18±15 to 1.0±0.7 µM) Study conducted in HIV-1 infected patients Rifabutin is not recommended for patients dosed with delavirdine mesylate 400 mg q8h.
Didanosine No significant change in kinetics. No significant change in kinetics at steady state.
Fosamprenavir/ritonavir 64% ↑ AUC - Drug plus active metabolite 35% ↑ AUC and 36% ↑ Cmax, no effect Ctrough (amprenavir) Dosage reduction of rifabutin by at least 75% (to 150 mg every other day or three times per week) is recommended when combined with fosamprenavir
Indinavir 204% ↑ in AUC 32%↓ in AUC
Lopinavir/ritonavir 5.7-fold ↑ AUC, 3.4 fold ↑ Cmax No significant change in lopinavir kinetics. Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted. Further dosage reduction of rifabutin may be necessary.
Saquinavir ND 40% ↓ in AUC
Ritonavir 4 fold increase in AUC, 2.5 fold increase in Cmax ND In the presence of ritonavir the subsequent risk of side effects, including uveitis may be increased . If a protease inhibitor is required in a patient treated with rifabutin, agents other than ritonavir should be considered.
Tipranavir/ritonavir[133] 2.9-fold ↑ AUC, 1.7-fold ↑ Cmax No significant change in tipranavir kinetics. Therapeutic drug monitoring of rifabutin is recommended.
Zidovudine No significant change in kinetics. Approximately 32%↓ in Cmax and AUC A large controlled clinical study has shown that these changes are of no clinical relevance.
ANTIFUNGALS
ANTIFUNGALS 82% ↑ in AUC No significant change in steady-state plasma concentrations
Itraconazole ND 70% to 75% ↓ in Cmax and AUC One case report suggests a kinetic interaction resulting in an increase in serum rifabutin levels and a risk for developing uveitis in the presence of itraconazole.
Posaconazole 31%↑ Cmax, 72%↑ AUC 43%↓ Cmax, 49%↓ AUC If the drugs are co-administered, patients should be monitored for adverse events associated with rifabutin administration.
Voriconazole 195%↑ Cmax, 331%↑ AUC - voriconazole dosed at 400 mg twice daily Rifabutin (300 mg once daily) decreased the Cmax and AUC of voriconazole at 200 mg twice daily by 69% and 78%, respectively. During co-administration with rifabutin, the Cmax and AUC of voriconazole at 350 mg twice daily were 96% and 68% of the levels when administered alone at 200 mg twice daily. At a voriconazole dose of 400 mg twice daily Cmax and AUC were 104% and 87% higher, respectively, compared with voriconazole alone at 200 mg twice daily. If the benefit outweighs the risk, rifabutin may be coadministered with voriconazole if the maintenance dose of voriconazole is increased to 5 mg/kg intravenously every 12 hours or from 200 mg to 350 mg orally, every 12 hours (100 mg to 200 mg orally, every 12 hours in patients less than 40 kg). Careful monitoring of full blood counts and adverse events to rifabutin (e.g. uveitis) is recommended when rifabutin is coadministered with voriconazole
ANTI-PCP (Pneumocystis carinii pneumonia)
Dapsone ND Approximately 27% to 40% ↓ in AUC Study conducted in HIV infected patients (rapid and slow acetylators).
Sulfamethoxazole-Trimethoprim No significant change in Cmax and AUC Approximately 15% to 20% ↓ in AUC In another study, only trimethoprim (not sulfamethoxazole) had 14% ↓ in AUC and 6%↓ in Cmax but were not considered clinically significant.
ANTI-MAC (Mycobacterium avium intracellulare complex)
Azithromycin No PK interaction No PK interaction
Clarithromycin Approximately 77% ↑ in AUC Approximately 50%↓ in AUC Study conducted in HIV infected patients. Dose of rifabutin should be adjusted in the presence of clarithromycin
ANTI-TB (Tuberculosis)
Ethambutol ND No significant change in AUC or Cmax
Isoniazid ND Pharmacokinetics not affected
Pyrazinamide ND ND Study data being evaluated.
OTHER
Methadone ND No significant effect No apparent effect of rifabutin on either peak levels of methadone or systemic exposure based upon AUC. Rifabutin kinetics not evaluated.
Ethinylestradiol ND 35%↓ AUC
20%↓ Cmax
Patients should be advised to use other methods of contraception.
Norethindrone ND 46%↓ AUC Patients should be advised to use other methods of contraception.
Tacrolimus ND ND Authors report that rifabutin decreases tacrolimus trough blood levels.
Theophylline ND No significant change in AUC or Cmax compared with baseline.


Table name:
Table 8: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s) Recommendation Comments
Tizanidine Contraindicated Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2) ]
Theophylline Avoid Use
(Plasma Exposure Likely to be Increased and Prolonged)
Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions (5.9) ].
Drugs Known to Prolong QT Interval Avoid Use Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.11) and Use in Specific Populations (8.5) ].
Oral antidiabetic drugs Use with caution
Glucose-lowering effect potentiated
Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs [see Adverse Reactions (6.1) ].
Phenytoin Use with caution
Altered serum levels of phenytoin (increased and decreased)
To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin with phenytoin.
Cyclosporine Use with caution
(transient elevations in serum creatinine)
Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs Use with caution
(Increase in anticoagulant effect)
The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anticoagulant (for example, warfarin).
Methotrexate Use with caution
Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels
Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole Use with caution Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin [see Warnings and Precautions (5.15) ].
Clozapine Use with caution Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs Use with caution Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil Use with caution
Two-fold increase in exposure
Monitor for sildenafil toxicity [see Clinical Pharmacology (12.3) ].
Duloxetine Avoid Use
Five-fold increase in duloxetine exposure
If unavoidable, monitor for duloxetine toxicity.
Caffeine/Xanthine Derivatives Use with caution
Reduced clearance resulting in elevated levels and prolongation of serum half-life
Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Probenecid Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels) Potentiation of ciprofloxacin toxicity may occur.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor
(boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
 Interacting Agents  Prescribing Recommendations
 Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)    Avoid atorvastatin  
 HIV protease inhibitor (lopinavir plus ritonavir)  Use with caution and lowest dose necessary
 Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)  Do not exceed 20 mg atorvastatin daily
  HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)  Do not exceed 40 mg atorvastatin daily


Table name:
Table 3 Clinically Significant Drug Interactions with Meloxicam
Drugs  that  Interfere  with  Hemostasis 
Clinical  Impact
Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. 
Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. 
Intervention

Monitor patients with concomitant use of Meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin 
Clinical  Impact
Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].
Intervention

Concomitant use of Meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. Meloxicam is not a substitute for low dose aspirin for cardiovascular protection.
ACE  Inhibitors Angiotensin  Receptor  Blockers or  Beta - Blockers 
Clinical  Impact
NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). 
In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, coadministration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. 
Intervention

During concomitant use of Meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.  During concomitant use of Meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics 
Clinical  Impact
Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. 
Intervention

During concomitant use of Meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Lithium 
Clinical  Impact
NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [see Clinical Pharmacology (12.3)].
Intervention

During concomitant use of Meloxicam and lithium, monitor patients for signs of lithium toxicity. 
Methotrexate 
Clinical  Impact
Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). 
Intervention

During concomitant use of Meloxicam and methotrexate, monitor patients for methotrexate toxicity. 
Cyclosporine 
Clinical  Impact
Concomitant use of Meloxicam and cyclosporine may increase cyclosporine's nephrotoxicity. 
Intervention

During concomitant use of Meloxicam and cyclosporine, monitor patients for signs of worsening renal function. 
NSAIDs  and  Salicylates 
Clinical  Impact
Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention

The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended. 
Pemetrexed 
Clinical  Impact
Concomitant use of Meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). 
Intervention

During concomitant use of Meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. 

Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. 

In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended. 


Table name:
Table 8:Effect of Voriconazole on Pharmacokinetics of Other Drugs [ see Clinical Pharmacology (12.3)]
Drug/Drug Class (Mechanism of Interaction by Voriconazole) Drug Plasma Exposure
(Cmax and AUCτ)
Recommendations for Drug Dosage Adjustment/Comments
* Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects
** Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects
*** Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for 4 days voriconazole to subjects receiving a methadone maintenance dose (30-100 mg q24h)
**** Non-Steroidal Anti-Inflammatory Drug
***** Non-Nucleoside Reverse Transcriptase Inhibitors
Sirolimus*
(CYP3A4 Inhibition)
Significantly Increased Contraindicated
Rifabutin*
(CYP3A4 Inhibition)
Significantly Increased Contraindicated
Efavirenz (400 mg q24h)**
(CYP3A4 Inhibition)
Significantly Increased Contraindicated
Efavirenz (300 mg q24h)** (CYP3A4 Inhibition) Slight Increase in AUCτ When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)** (CYP3A4 Inhibition) No Significant Effect of Voriconazole on Ritonavir Cmax or AUCτ Contraindicated because of significant reduction of voriconazole Cmax and AUCτ
Low-dose Ritonavir (100 mg q12h)** Slight Decrease in Ritonavir Cmax and AUCτ Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole Cmax and AUCτ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine
(CYP3A4 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids
(CYP450 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Contraindicated
Cyclosporine*
(CYP3A4 Inhibition)
AUCτ Significantly Increased; No Significant Effect on Cmax When initiating therapy with voriconazole tablets in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When voriconazole tablets are discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
Methadone***
(CYP3A4 Inhibition)
Increased Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl
(CYP3A4 Inhibition)
Increased Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole tablets. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7)]
Alfentanil
(CYP3A4 Inhibition)
Significantly Increased Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with voriconazole tablets. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [see Drug Interactions (7)].
Oxycodone
(CYP3A4 Inhibition)
Significantly Increased Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole tablets. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7)].
NSAIDs**** including. ibuprofen and diclofenac
(CYP2C9 Inhibition)
Increased Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed [see Drug Interactions (7)].
Tacrolimus*
(CYP3A4 Inhibition)
Significantly Increased When initiating therapy with voriconazole tablets in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazole tablets are discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin*
(CYP2C9 Inhibition)
Significantly Increased Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone
(CYP3A4 Inhibition)**
Increased Monitoring for adverse events related to oral contraceptives is recommended during coadministration
Warfarin*
(CYP2C9 Inhibition)
Prothrombin Time Significantly Increased Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed.
Omeprazole*
(CYP2C19/3A4 Inhibition)
Significantly Increased When initiating therapy with voriconazole tablets in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors
(CYP3A4 Inhibition)
In Vivo Studies Showed No Significant Effects on Indinavir Exposure In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) No dosage adjustment for indinavir when coadministered with voriconazole tablets Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors
Other NNRTIs*****
(CYP3A4 Inhibition)
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs
(Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity related to NNRTI
Benzodiazepines
(CYP3A4 Inhibition)
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
HMG-CoA Reductase Inhibitors (Statins)
(CYP3A4 Inhibition)
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers
(CYP3A4 Inhibition)
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics
(CYP2C9 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids
(CYP3A4 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed.
Everolimus
(CYP3A4 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Concomitant administration of voriconazole and everolimus is not recommended.


Table name:
Table 3: Clinically Significant Drug Interactions with Celecoxib
 Drugs That Interfere w ith Hemostasis
Clinical Impact:
Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of Celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:
Monitor patients with concomitant use of celecoxib with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11) ].
 Aspirin
Clinical Impact:
Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2) ].
In two studies in healthy volunteers, and in patients with osteoarthritis and established heart disease respectively, celecoxib (200 to 400 mg daily) has demonstrated a lack of interference with the cardioprotective antiplatelet effect of aspirin (100 to 325 mg).
Intervention:
Concomitant use of celecoxib and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11) ].
Celecoxib is not a substitute for low dose aspirin for cardiovascular protection.
 ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:
NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:
During concomitant use of celecoxib and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of celecoxib and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6) ]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
 Diuretics
Clinical Impact:
Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:
During concomitant use of celecoxib with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6) ].
 Digoxin
Clinical Impact:
The concomitant use of Celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:
During concomitant use of celecoxib and digoxin, monitor serum digoxin levels.
 Lithium
Clinical Impact:
NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:
During concomitant use of celecoxib and lithium, monitor patients for signs of lithium toxicity.
 Methotrexate
Clinical Impact:
Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Celecoxib has no effect on methotrexate pharmacokinetics.
Intervention:
During concomitant use of celecoxib and methotrexate, monitor patients for methotrexate toxicity.
 Cyclosporine
Clinical Impact:
Concomitant use of celecoxib and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:
During concomitant use of celecoxib and cyclosporine, monitor patients for signs of worsening renal function.
 NSAIDs a nd Salicylates
Clinical Impact:
Concomitant use of Celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2) ].
Intervention:
The concomitant use of Celecoxib with other NSAIDs or salicylates is not recommended.
 Pemetrexed
Clinical Impact:
Concomitant use of celecoxib and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:
During concomitant use of celecoxib and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.
NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.
In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
 CYP2C9 Inhibitors or inducers
Clinical Impact:
Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Co­-administration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of celecoxib.
Intervention
Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers. [see Clinical Pharmacology (12.3) ].
 CYP2D6 substrates
Clinical Impact:
In vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6 (e.g. atomoxetine), and celecoxib may enhance the exposure and toxicity of these drugs.
Intervention
Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2D6 substrates. [see Clinical Pharmacology (12.3) ].
 Corticosteroids
Clinical Impact:
Concomitant use of corticosteroids with celecoxib may increase the risk of GI ulceration or bleeding.
Intervention
Monitor patients with concomitant use of celecoxib with corticosteroids for signs of bleeding [see Warnings and Precautions (5.2) ].


Table name:
Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug Dosing Schedule Effect on Active Moiety (Risperidone + 9Hydroxy- Risperidone (RatioChange relative to reference) Risperidone Dose Recommendation
Coadministered Drug Risperidone AUC Cmax
Enzyme (CYP2D6) Inhibitors
Fluoxetine 20 mg/day 2 or 3 mg twice daily 1.4 1.5 Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine 10 mg/day 4 mg/day 1.3 - Re-evaluate dosing. Do not exceed 8 mg/day
20 mg/day 4 mg/day 1.6 -
40 mg/day 4 mg/day 1.8 -
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine 573 ± 168 mg/day 3 mg twice daily 0.51 0.55 Titrate dose upwards. Do not exceed twice the patient's usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine 150 mg twice daily 1 mg single dose 1.2 1.4 Dose adjustment not needed
Cimetidine 400 mg twice daily 1 mg single dose 1.1 1.3 Dose adjustment not needed
Erythromycin 500 mg four times daily 1 mg single dose 1.1 0.94 Dose adjustment not needed
Other Drugs
Amitriptyline 50 mg twice daily 3 mg twice daily 1.2 1.1 Dose adjustment not needed


Table name:
 Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
 Interacting Agents  Prescribing Recommendations
 Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)  Avoid atorvastatin
 HIV protease inhibitor (lopinavir plus ritonavir)  Use with caution and lowest dose necessary
 Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)  Do not exceed 20 mg atorvastatin daily
 HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
 Do not exceed 40 mg atorvastatin daily


Table name:
Table 3: Clinically Relevant Interactions Affecting Drugs Co-Administered with Omeprazole and Interaction with Diagnostics
Antiretrovirals
Clinical Impact:
The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology ( 12.3)]. Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see Clinical Pharmacology (12.3)]. There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole.
Intervention:
Rilpivirine-containing products: Concomitant use with omeprazole is contraindicated [see Contraindications ( 4)] .
 
Atazanavir: Avoid concomitant use with omeprazole. See prescribing information for atazanavir for dosing information.
 
Nelfinavir: Avoid concomitant use with omeprazole. See prescribing information for nelfinavir.
 
Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities.
 
Other antiretrovirals: See prescribing information for specific antiretroviral drugs.
Warfarin
Clinical Impact:
Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
Intervention:
Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range.
Methotrexate
Clinical Impact:
Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions ( 5.11)].
Intervention:
A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate.
CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam)
Clopidogrel
Clinical Impact:
Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology ( 12.3)].
There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel .
Intervention:
Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy [see Warnings and Precautions ( 5.6)].
Citalopram
Clinical Impact:
Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology ( 12.3)] .
Intervention:
Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.
Cilostazol
Clinical Impact:
Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology ( 12.3)].
Intervention:
Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.
Phenytoin
Clinical Impact:
Potential for increased exposure of phenytoin.
Intervention:
Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin.
Diazepam
Clinical Impact:
Increased exposure of diazepam [see Clinical Pharmacology ( 12.3)] .
Intervention:
Monitor patients for increased sedation and reduce the dose of diazepam as needed.
Digoxin
Clinical Impact:
Potential for increased exposure of digoxin [see Clinical Pharmacology ( 12.3)].
Intervention:
Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)
Clinical Impact:
Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
Intervention:
Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF [see Clinical Pharmacology ( 12.3)] .
 
See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact:
Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions.
Intervention:
See Contraindications, Warnings and Precautions  in prescribing information for clarithromycin.
 
See  Drug Interactions in prescribing information for amoxicillin.
Tacrolimus
Clinical Impact:
Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19 .
Intervention:
Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact:
Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions ( 5.10), Clinical Pharmacology ( 12.2)] .
Intervention:
Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
Interaction with Secretin Stimulation Test
Clinical Impact:
Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention:
Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology ( 12.2)] .
False Positive Urine Tests for THC
Clinical Impact:
There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.
Intervention:
An alternative confirmatory method should be considered to verify positive results.
Other
Clinical Impact:
There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram).
Intervention:
Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole.


Table name:
Drugs That Interfere with Hemostasis
Clinical Impact: • Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of naproxen or naproxen sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: Concomitant use of naproxen or naproxen sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen or naproxen sodium is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE-inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: • During concomitant use of naproxen or naproxen sodium and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of naproxen or naproxen sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen or naproxen sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact: The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of naproxen or naproxen sodium and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen or naproxen sodium and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of naproxen or naproxen sodium and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of naproxen or naproxen sodium and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of naproxen or naproxen sodium and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of naproxen or naproxen sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of naproxen or naproxen sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact: Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention: Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen or naproxen sodium is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed release tablets are not recommended.
Cholestyramine
Clinical Impact: Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention: Concomitant administration of cholestyramine with naproxen or naproxen sodium is not recommended.
Probenecid
Clinical Impact: Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention: Patients simultaneously receiving naproxen or naproxen sodium and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact: Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention: Patients simultaneously receiving naproxen or naproxen sodium and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.


Table name:
DRUG DESCRIPTION OF INTERACTION
Sulfonylureas Hypoglycemia potentiated.
Methotrexate Decreases tubular reabsorption; clinical toxicity from methotrexate can result.
Oral Anticoagulants Increased bleeding.


Table name:
 Antiretrovirals
Clinical Impact:   The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known.
• Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology (12.3)].
• Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see Clinical Pharmacology (12.3)].
• There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole.
Intervention:   Rilpivirine-containing products: Concomitant use with omeprazole is contraindicated [see Contraindications (4)].
Atazanavir: Avoid concomitant use with omeprazole. See prescribing information for atazanavir for dosing information.
Nelfinavir: Avoid concomitant use with omeprazole. See prescribing information for nelfinavir.
Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities.
Other antiretrovirals: See prescribing information for specific antiretroviral drugs.
 Warfarin
Clinical Impact:   Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.  
Intervention:   Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range.  
 Methotrexate
Clinical Impact:   Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions (5.11)].
Intervention:   A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate.
 CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam)
 Clopidogrel
Clinical Impact:   Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology (12.3)].
There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel.
Intervention:   Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy [see Warnings and Precautions (5.6)].
Citalopram
Clinical Impact: Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology (12.3)].
Intervention:   Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.
Cilostazol
Clinical Impact: Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology (12.3)].
Intervention:   Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.
Phenytoin
Clinical Impact: Potential for increased exposure of phenytoin.
Intervention:   Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin.
Diazepam
Clinical Impact:   Increased exposure of diazepam [see Clinical Pharmacology (12.3)].
Intervention:   Monitor patients for increased sedation and reduce the dose of diazepam as needed.
Digoxin
Clinical Impact:   Potential for increased exposure of digoxin [see Clinical Pharmacology (12.3)].
Intervention:   Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information.  
 Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)
Clinical Impact:   Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
Intervention:   Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF [see Clinical Pharmacology (12.3)]. See the prescribing information for other drugs dependent on gastric pH for absorption.
 Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact:   Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions.
Intervention:   See Contraindications, Warnings and Precautions in prescribing information for clarithromycin. See Drug Interactions in prescribing information for amoxicillin.
 Tacrolimus
Clinical Impact:   Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.
Intervention:   Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
 Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact:   Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions (5.10),Clinical Pharmacology (12.2)].
Intervention:   Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
Interaction with Secretin Stimulation Test  
Clinical Impact:   Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention:   Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology (12.2)].
False Positive Urine Tests for THC
Clinical Impact:   There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.
Intervention:   An alternative confirmatory method should be considered to verify positive results.
Other
Clinical Impact:   There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram).
Intervention:   Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole.


Table name:
Table 4: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s) Recommendation Comments
Tizanidine Contraindicated Concomitant administration of tizanidine and ciprofloxacin extended-release tablets is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)].
Theophylline Avoid use (Plasma exposure likely to be increased and prolonged) Concurrent administration of ciprofloxacin extended-release tablets with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions (5.9) ].
Drugs Known to Prolong QT Interval Avoid use Ciprofloxacin extended-release tablets may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.11) and Use in Specific Populations (8.5)].
Oral Antidiabetic Drugs Use with caution Glucose-lowering effect potentiated Hypoglycemia sometimes severe has been reported when ciprofloxacin extended-release tablets and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin extended-release tablets are co-administered with oral antidiabetic drugs [see Adverse Reactions (6.1)].
Phenytoin Use with caution Altered serum levels of phenytoin (increased and decreased) To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin extended-release tablets discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin extended-release tablets with phenytoin.
Cyclosporine Use with caution (Transient elevations in serum creatinine) Monitor renal function (in particular serum creatinine) when ciprofloxacin extended-release tablets are co-administered with cyclosporine.
Anticoagulant Drugs Use with caution (Increase in anticoagulant effect) The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin extended-release tablets to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin extended-release tablets with an oral anticoagulant (for example, warfarin).
Methotrexate Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin extended-release tablets therapy is indicated.
Ropinirole Use with caution Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin extended-release tablets [see Warnings and Precautions (5.15)].
Clozapine Use with caution Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin extended-release tablets is advised.
NSAIDs Use with caution Nonsteroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil Use with caution 2-fold increase in exposure Monitor for sildenafil toxicity [see Clinical Pharmacology (12.3) ].
Duloxetine Avoid use 5-fold increase in duloxetine exposure If unavoidable, monitor for duloxetine toxicity.
Caffeine/Xanthine Derivatives Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life Ciprofloxacin extended-release tablets inhibit the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin Extended-Release Tablets
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products) Ciprofloxacin extended-release tablets should be taken at least 2 hours before or 6 hours after multivalent cation-containing products administration [see Dosage and Administration (2)] Decrease ciprofloxacin extended-release tablets absorption, resulting in lower serum and urine levels considerably lower than desired for concurrent administration of these agents with ciprofloxacin extended-release.
Probenecid Use with caution (Interferes with renal tubular secretion of ciprofloxacin extended-release tablets and increases ciprofloxacin extended-release tablets serum levels) Potentiation of ciprofloxacin extended-release tablets toxicity may occur.


Table name:
Table 2: Drug-Thyroidal Axis Interactions
   Drug or Drug Class    Effect
   Drugs that may reduce TSH secretion–the reduction is not sustained; therefore, hypothyroidism does not occur
   Dopamine / Dopamine Agonists
Glucocorticoids
Octreotide
   Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day).
   Drugs that alter thyroid hormone secretion
   Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
   Aminoglutethimide
Amiodarone
Iodide(including iodine-containing
  Radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
   Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients.  The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
   Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
   Amiodarone
Iodide(including iodine-containing   
  Radiographic contrast agents)
   Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma).  Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
   Drugs that may decrease T 4 absorption, which may result in hypothyroidism
   Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
   Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism.  Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents.  Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
   Drugs that may alter T 4 and T 3 serum transport  - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
   Drugs that may increase serum TBG concentration    Drugs that may decrease serum TBG concentration
   Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
   Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
   Drugs that may cause protein-binding site displacement
   Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
   Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4, and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
   Drugs that may alter T 4 and T 3 metabolism
   Drugs that may increase hepatic metabolism, which may result  in hypothyroidism
   Carbamazepine
Hydantoins
Phenobarbital
Rifampin
   Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
   Drugs that may decrease T 4 5’-deiodinase activity
   Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
   Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4  levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
   Miscellaneous
   Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
   Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
   Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors
  (SSRIs; e.g., Sertraline)
   Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of  tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
   Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
   Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
   Cardiac Glycosides    Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
   Cytokines
- Interferon-α
- Interleukin-2
   Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
   Growth Hormones
- Somatrem
- Somatropin
   Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
   Ketamine    Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
   Methylxanthine Bronchodilators
- (e.g., Theophylline)
   Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
   Radiographic Agents    Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
   Sympathomimetics    Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
   Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
   These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.


Table name:
Table 2: Clinically Significant Drug Interactions with Diclofenac
Drugs That Interfere with Hemostasis
Clinical Impact: Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of diclofenac with anticoagulants (e.g., warfarin), antiplatelet agents
(e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding ( see PRECAUTIONS; Hematological Toxicity ).
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see
WARNINGS; Gastrointestinal Bleeding, Ulceration, and Perforation) .
Intervention: Concomitant use of diclofenac and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding ( see PRECAUTIONS: Hematological Toxicity ).
Diclofenac is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible
Intervention: During concomitant use of diclofenac and ACE-inhibitors, ARBs, or betablockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of diclofenac and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function ( see WARNINGS; Renal Toxicity and Hyperkalemia ). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of diclofenac with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects ( see WARNINGS; Renal Toxicity and Hyperkalemia ).
Digoxin
Clinical Impact: The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of diclofenac and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of diclofenac and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of diclofenac and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of diclofenac and cyclosporine may increase cyclosporine's nephrotoxicity.
Intervention: During concomitant use of diclofenac and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy ( see WARNINGS; Gastrointestinal Bleeding, Ulceration, and Perforation ).
Intervention: The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of diclofenac and pemetrexed may increase the risk of pemetrexedassociated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of diclofenac and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.
NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.
In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
CYP2C9 Inhibitors or Inducers:
Clinical Impact: Diclofenac is metabolized by cytochrome P450 enzymes, predominantly by CYP2C9. Co-administration of diclofenac with CYP2C9 inhibitors (e.g. voriconazole) may enhance the exposure and toxicity of diclofenac whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of diclofenac.
Intervention: A dosage adjustment may be warranted when diclofenac is administered with CYP2C9 inhibitors or inducers ( see CLINICAL PHARMACOLOGY; Pharmacokinetics ).


Table name:
Drugs That Interfere with Hemostasis
Clinical Impact Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention Monitor patients with concomitant use of diclofenac sodium topical solution with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)]
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of NSAID alone [see Warnings and Precautions (5.2)]
Intervention Concomitant use of diclofenac sodium topical solution and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. Diclofenac sodium topical solution is not a substitute for low dose aspirin for cardiovascular protection.
ACE inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: During concomitant use of diclofenac sodium topical solution and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of diclofenac sodium topical solution and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions(5.6)] When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDS reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of diclofenac sodium topical solution with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Digoxin
Clinical Impact: The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life digoxin.
Intervention: During concomitant use of diclofenac sodium topical solution and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDS have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of diclofenac sodium topical solution and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact; Concomitant use of NSAIDs and methotrexate may increase the risk of methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of diclofenac sodium topical solution and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of diclofenac sodium topical solution and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of diclofenac sodium topical solution and cyclosporine, monitor patients for signs or worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)]. Concomitant use of oral NSAIDs with diclofenac sodium topical solution has been evaluated in one Phase 3 controlled trial and in combination with oral diclofenac, compared to oral diclofenac alone, resulted in a higher rate of rectal hemorrhage (3% vs. less than 1%), and more frequent abnormal creatinine (12% vs. 7%), urea (20% vs. 12%) and hemoglobin (13% vs. 9%).
Intervention: The concomitant use of diclofenac with other NSAIDs or salicyclates is not recommended. Do not use combination therapy with diclofenac sodium topical solution and an oral NSAID unless the benefit outweighs the risk and conduct periodic laboratory evaluations
Pemetrexed
Clinical Impact: Concomitant use of diclofenac sodium topical solution and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of diclofenac sodium topical solution and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives 9e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.


Table name:
Drug/Drug Class (Mechanism of Interaction by Voriconazole) Drug Plasma Exposure
(Cmax and AUCτ)
Recommendations for Drug Dosage Adjustment/Comments
Sirolimus*
(CYP3A4 Inhibition)
Significantly Increased Contraindicated
Rifabutin*
(CYP3A4 Inhibition)
Significantly Increased Contraindicated
Efavirenz (400 mg q 24h)**
(CYP3A4 Inhibition)
Efavirenz (300 mg q 24h) ** (CYP3A4 Inhibition)
Significantly Increased Slight decrease in AUCt Contraindicated When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)**(CYP3A4 Inhibition)
No Significant Effect of Voriconazole on Ritonavir Cmax or AUCτ Contraindicated because of significant reduction of voriconazole Cmax and AUCτ
Low-dose Ritonavir (100 mg q12h)** Slight Decrease in Ritonavir Cmax and AUCτ Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole Cmax and AUCτ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids
(CYP450 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Contraindicated
Cyclosporine*
(CYP3A4 Inhibition)
AUCτ Significantly Increased; No Significant Effect on Cmax When initiating therapy with voriconazole in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When voriconazole is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
Methadone***
(CYP3A4 Inhibition)
Increased Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl
(CYP3A4 Inhibition)
Increased Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7) ]
Alfentanil
(CYP3A4 Inhibition)
Significantly Increased Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with voriconazole. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [see Drug Interactions (7) ].
Oxycodone
(CYP3A4 Inhibition)
Significantly Increased Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7) ].
NSAIDs**** including ibuprofen and diclofenac (CYP2C9 Inhibition) Increased Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed. [see Drug Interactions (7) ].
Tacrolimus* (CYP3A4 Inhibition) Significantly Increased When initiating therapy with voriconazole in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazole is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin* (CYP2C9 Inhibition) Significantly Increased Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)** Increased Monitoring for adverse events related to oral contraceptives is recommended during coadministration.
Warfarin* (CYP2C9 Inhibition) Prothrombin Time Significantly Increased Monitor PT or other suitable anticoagulation tests. Adjustment of warfarin dosage may be needed.
Omeprazole* (CYP2C19/3A4 Inhibition) Significantly Increased When initiating therapy with voriconazole in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors (CYP3A4 Inhibition) In Vivo Studies Showed No Significant Effects on Indinavir Exposure No dosage adjustment for indinavir when coadministered with voriconazole
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors
Other NNRTIs***** (CYP3A4 Inhibition) A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to NNRTI
Benzodiazepines (CYP3A4 Inhibition) In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.
HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition) In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition) In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition) Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed.
Everolimus (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Concomitant administration of voriconazole and everolimus is not recommended


Table name:
Inhibitors of CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6
Clinical Impact: Methadone undergoes hepatic N-demethylation by several cytochrome P450 (CYP) isoforms, including CYP3A4, CYP2B6, CYP2C19, CYP2C9, and CYP2D6. The concomitant use of methadone hydrochloride tablets for oral suspension and CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitors can increase the plasma concentration of methadone, resulting in increased or prolonged opioid effects, and may result in a fatal overdose, particularly when an inhibitor is added after a stable dose of methadone hydrochloride tablets for oral suspension is achieved. These effects may be more pronounced with concomitant use of drugs that inhibit more than one of the CYP enzymes listed above. After stopping a CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitor, as the effects of the inhibitor decline,
the methadone plasma concentration can decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy or withdrawal symptoms in patients physically dependent on methadone.
Intervention: If concomitant use is necessary, consider dosage reduction of methadone hydrochloride tablets for oral suspension until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitor is discontinued, follow patients for signs of opioid withdrawal and consider increasing the methadone hydrochloride tablets for oral suspension dosage until stable drug effects are achieved.
Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir), fluconazole, fluvoxamine, some selective serotonin reuptake inhibitors (SSRIs) (e.g., sertraline, fluvoxamine)
Inducers of CYP3A4, CYP2B6, CYP2C19, or CYP2C9
Clinical Impact: The concomitant use of methadone hydrochloride tablets for oral suspension and CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers can decrease the plasma concentration of methadone [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of withdrawal symptoms in patients physically dependent on methadone. These effects could be more pronounced with concomitant use of drugs that can induce multiple CYP enzymes. After stopping a CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducer, as the effects of the inducer decline, the methadone plasma concentration can increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression, sedation, or death.
Intervention: If concomitant use is necessary, consider increasing the methadone hydrochloride tablets for oral suspension dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducer is discontinued, consider methadone hydrochloride tablets for oral suspension dosage reduction and monitor for signs of respiratory depression and sedation.
Examples: Rifampin, carbamazepine, phenytoin, St. John’s Wort, Phenobarbital
Potentially Arrhythmogenic Agents
Clinical Impact: Pharmacodynamic interactions may occur with concomitant use of methadone and potentially arrhythmogenic agents or drugs capable of inducing electrolyte disturbances (hypomagnesemia, hypokalemia).
Intervention: Monitor patients closely for cardiac conduction changes.
Examples: Drugs known to have potential to prolong QT interval: Class I and III antiarrhythmics, some neuroleptics and tricyclic antidepressants, and calcium channel blockers. Drugs capable of inducing electrolyte disturbances: Diuretics, laxatives, and, in rare cases, mineralocorticoid hormones.
Central Nervous System (CNS) Depressants
Clinical Impact: Due to additive pharmacologic effect, the concomitant use of CNS depressants can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention: Consider dose reduction of one or both drugs. Monitor patients for respiratory depression, sedation, and hypotension [see Warnings and Precautions (5.8)].
Examples: Alcohol, benzodiazepines, and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids.
Serotonergic Drugs
Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Warnings and Precautions (5.9)].
Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue methadone hydrochloride tablets for oral suspension if serotonin syndrome is suspected.
Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.1)].
Intervention: The use of methadone hydrochloride tablets for oral suspension is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples: phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact: Patients maintained on methadone may experience withdrawal symptoms when given opioid antagonists, mixed agonist/antagonists, and partial agonists.
Intervention: Avoid concomitant use.
Examples: butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact: Methadone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of methadone hydrochloride tablets for oral suspension and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when methadone hydrochloride tablets for oral suspension is used concomitantly with anticholinergic drugs.


Table name:
Table 1: Clinically Significant Drug Interactions with Piroxicam
Drugs  That  Interfere  with  Hemostasis
Clinical Impact:
( Piroxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of piroxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. 
( Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:
Monitor patients with concomitant use of Piroxicam Capsules USP with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact:
Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].
Intervention:
Concomitant use of Piroxicam Capsules USP and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. Piroxicam Capsules USP is not a substitute for low dose aspirin for cardiovascular protection.
ACE  Inhibitors Angiotensin  Receptor  Blockers and  Beta - Blockers
Clinical Impact:
NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).
In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:
During concomitant use of Piroxicam Capsules USP and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of Piroxicam Capsules USP and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:
Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:
During concomitant use of Piroxicam Capsules USP with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Digoxin
Clinical Impact:
The concomitant use of piroxicam with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:
During concomitant use of Piroxicam Capsules USP and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:
NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:
During concomitant use of Piroxicam Capsules USP and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:
Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:
During concomitant use of Piroxicam Capsules USP and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:
Concomitant use of Piroxicam Capsules USP and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:
During concomitant use of Piroxicam Capsules USP and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs  and  Salicylates
Clinical Impact:
Concomitant use of piroxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention:
The concomitant use of piroxicam with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:
Concomitant use of Piroxicam Capsules USP and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:
During concomitant use of Piroxicam Capsules USP and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.

NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. 

In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Highly  Protein  Bound  Drugs
Clinical Impact:
Piroxicam Capsules USP is highly protein bound and, therefore, might be expected to displace other protein bound drugs.
Intervention:
Physicians should closely monitor patients for a change in dosage requirements when administering Piroxicam Capsules USP to patients on other highly protein bound drugs.
Corticosteroids
Clinical Impact:
Concomitant use of corticosteroids with Piroxicam Capsules USP may increase the risk of GI ulceration or bleeding.
Intervention:
Monitor patients with concomitant use of Piroxicam Capsules USP with corticosteroids for signs of bleeding [see Warnings and Precautions (5.2)].


Table name:
Table 18. Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
*Change relative to reference
Coadministered Drug
 
Dosing Schedule
Effect on Active Moiety
(Risperidone + 9- Hydroxy-
Risperidone (Ratio*)
Risperidone Dose
Recommendation
Coadministered Drug
Risperidone
AUC
Cmax
Enzyme (CYP2D6) inhibitors
 
 
 
 
Fluoxetine
20 mg/day
2 or 3 mg twice daily
1.4
1.5

Re-evaluate dosing.
Do not exceed 8 mg/day
Paroxetine
10 mg/day
4 mg/day
1.3
-

Re-evaluate dosing.
Do not exceed 8 mg/day
20 mg/day
4 mg/day
1.6
-
40 mg/day
4 mg/day
1.8
-
Enzyme (CYP3A/ PgP inducers) Inducers
 
 
 
 
 
Carbamazepine
573 ± 168 mg/day
 
3 mg twice daily
 
0.51
 
0.55
 

Titrate dose upwards.
Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) inhibitors
 
 
 
 
 
Ranitidine
150 mg twice daily
1 mg single dose
1.2
1.4
Dose adjustment not needed
Cimetidine
400 mg twice daily
1 mg single dose
1.1
1.3
Dose adjustment not needed
Erythromycin
500 mg four times daily
1 mg single dose
1.1
0.94
Dose adjustment not needed
Other Drugs
 
 
 
 
 
Amitriptyline
50 mg twice daily
3 mg twice daily
1.2
1.1
Dose adjustment not Needed


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine Do not exceed 10 mg atorvastatin daily
Clarithromycin, itraconazole, HIV protease inhibitors (ritonavir plus saquinavir or lopinavir plus ritonavir) Caution when exceeding doses > 20 mg atorvastatin daily. The lowest dose necessary should be used.


Table name:
Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
NA – Not available/reported
Digoxin concentrations increased greater than 50%
   Digoxin Serum   
Concentration Increase
   Digoxin AUC   
Increase
Recommendations
Amiodarone 70% NA Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring.
Captopril 58% 39%
Clarithromycin NA 70%
Dronedarone NA 150%
Gentamicin 129-212% NA
Erythromycin 100% NA
Itraconazole 80% NA
Nitrendipine 57% 15%
Propafenone NA 60-270%
Quinidine 100% NA
Ranolazine 50% NA
Ritonavir NA 86%
Tetracycline 100% NA
Verapamil 50-75% NA
Digoxin concentrations increased less than 50%
Atorvastatin 22% 15% Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring.
Carvedilol 16% 14%
Diltiazem 20% NA
Indomethacin 40% NA
Nefazodone 27% 15%
Nifedipine 45% NA
Propantheline 24% 24%
Quinine NA 33%
Saquinavir 27% 49%
Spironolactone      25% NA
Telmisartan 20-49% NA
Tolvaptan 30% NA
Trimethoprim 22-28% NA
Digoxin concentrations increased, but magnitude is unclear
Alprazolam, azithromycin, cyclosporine, diclofenac,
diphenoxylate, epoprostenol, esomeprazole, ibuprofen,
ketoconazole, lansoprazole, metformin, omeprazole,
rabeprazole,
Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin concentrations decreased
Acarbose, activated charcoal, albuterol, antacids, certain
cancer chemotherapy or radiation therapy, cholestyramine,
colestipol, extenatide, kaolin-pectin, meals high in bran,
metoclopramide, miglitol, neomycin, penicillamine,
phenytoin, rifampin, St. John’s Wort, sucralfate,
sulfasalazine
Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20-40% as necessary.
No significant Digoxin exposure changes
Please refer to section 12 for a complete list of drugs which     
were studied but reported no significant changes on digoxin exposure.
No additional actions are required.     


Table name:
Antiretrovirals
        Clinical Impact: The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology ( 12.3)] . Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see Clinical Pharmacology ( 12.3)] . There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole.
        Intervention: Rilpivirine-containing products: Concomitant use with omeprazole is contraindicated [see Contraindications ( 4)] .

Atazanavir: Avoid concomitant use with omeprazole. See prescribing information for atazanavir for dosing information.

Nelfinavir: Avoid concomitant use with omeprazole. See prescribing information for nelfinavir.

Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities.

Other antiretrovirals: See prescribing information for specific antiretroviral drugs.
Warfarin
Clinical Impact: Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
Intervention: Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range.
Methotrexate
Clinical Impact: Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions ( 5.11)] .
Intervention: A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate.
CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam)
Clopidogrel
Clinical Impact: Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology ( 12.3)] .

There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel.
Intervention: Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy [see Warnings and Precautions ( 5.6)] .
Citalopram
Clinical Impact: Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology ( 12.3)] .
Intervention: Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.
Cilostazol
Clinical Impact: Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology ( 12.3)] .
Intervention: Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.
Phenytoin
Clinical Impact: Potential for increased exposure of phenytoin.
Intervention: Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin.
Diazepam
Clinical Impact: Increased exposure of diazepam [see Clinical Pharmacology ( 12.3)] .
Intervention: Monitor patients for increased sedation and reduce the dose of diazepam as needed.
Digoxin
Clinical Impact: Potential for increased exposure of digoxin [see Clinical Pharmacology ( 12.3)] .
Intervention: Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)
Clinical Impact: Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
     Intervention: Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF [see Clinical Pharmacology ( 12.3)] .

See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact: Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated.
Amoxicillin also has drug interactions.
Intervention: See Contraindications, Warnings and Precautions in prescribing information for clarithromycin.

See Drug Interactions in prescribing information for amoxicillin.
Tacrolimus
Clinical Impact: Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.
Intervention: Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact: Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions ( 5.10), Clinical Pharmacology ( 12.2)] .
  Intervention: Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
Interaction with Secretin Stimulation Test
Clinical Impact: Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention: Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology ( 12.2)] .
False Positive Urine Tests for THC
Clinical Impact: There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.
Intervention: An alternative confirmatory method should be considered to verify positive results.
Other
Clinical Impact: There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram).
Intervention: Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole.


Table name:
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:
The concomitant use of SSRIs including sertraline hydrochloride and MAOIs increases the risk of serotonin syndrome.
Intervention:
Sertraline hydrochloride is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [See Dosage and Administration (2.5), Contraindications (4), Warnings and Precautions (5.2)].
Examples:
selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue
Pimozide
Clinical Impact:
Increased plasma concentrations of pimozide, a drug with a narrow therapeutic index, may increase the risk of QT prolongation and ventricular arrhythmias.
Intervention:
Concomitant use of pimozide and sertraline hydrochloride is contraindicated [See Contraindications (4)].
Other Serotonergic Drugs
Clinical Impact:
The concomitant use of serotonergic drugs with sertraline hydrochloride increases the risk of serotonin syndrome.
Intervention:
Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of sertraline hydrochloride and/or concomitant serotonergic drugs [See Warnings and Precautions (5.2)].
Examples:
other SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort
Drugs that Interfere with Hemostasis (antiplatelet agents and anticoagulants)
Clinical Impact:
The concurrent use of an antiplatelet agent or anticoagulant with sertraline hydrochloride may potentiate the risk of bleeding.
Intervention:
Inform patients of the increased risk of bleeding associated with the concomitant use of sertraline hydrochloride and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio [See Warnings and Precautions (5.3)].
Examples:
aspirin, clopidogrel, heparin, warfarin
Drugs Highly Bound to Plasma Protein
Clinical Impact:
Sertraline hydrochloride is highly bound to plasma protein. The concomitant use of sertraline hydrochloride with another drug that is highly bound to plasma protein may increase free concentrations of sertraline hydrochloride or other tightly-bound drugs in plasma [See Clinical Pharmacology (12.3)].
Intervention:
Monitor for adverse reactions and reduce dosage of sertraline hydrochloride or other protein-bound drugs as warranted.
Examples:
warfarin
Drugs Metabolized by CYP2D6
Clinical Impact:
Sertraline hydrochloride is a CYP2D6 inhibitor [See Clinical Pharmacology (12.3)]. The concomitant use of sertraline hydrochloride with a CYP2D6 substrate may increase the exposure of the CYP2D6 substrate.
Intervention:
Decrease the dosage of a CYP2D6 substrate if needed with concomitant sertraline hydrochloride use. Conversely, an increase in dosage of a CYP2D6 substrate may be needed if sertraline hydrochloride is discontinued.
Examples:
propafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, thoridazine, tolterodine, venlafaxine
Phenytoin
Clinical Impact:
Phenytoin is a narrow therapeutic index drug. sertraline hydrochloride may increase phenytoin concentrations.
Intervention:
Monitor phenytoin levels when initiating or titrating sertraline hydrochloride. Reduce phenytoin dosage if needed.
Examples:
phenytoin, fosphenytoin


Table name:
NA = Not available/reported
Digoxin concentrations increased greater than 50%
   Digoxin Serum   
Concentration Increase
   Digoxin AUC Increase Recommendations
Amiodarone 70% NA Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring.
Captopril 58% 39%
Clarithromycin NA 70%
Dronedarone NA 150%
Gentamicin 129-212% NA
Erythromycin 100% NA
Itraconazole 80% NA
Lapatinib NA 180%
Nitrendipine 57% 15%
Propafenone NA 60-270%
Quinidine 100% NA
Ranolazine 50% NA
Ritonavir NA 86%
Telaprevir 50% 85%
Tetracycline 100% NA
Verapamil 50-75% NA
Digoxin concentrations increased less than 50%
Atorvastatin 22% 15% Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring.
Carvedilol 16% 14%
Conivaptan 33% 43%
Diltiazem 20% NA
Indomethacin 40% NA
Nefazodone 27% 15%
Nifedipine 45% NA
Propantheline 24% 24%
Quinine NA 33%
Rabeprazole 29% 19%
Saquinavir 27% 49%
Spironolactone      25% NA
Telmisartan 20-49% NA
Ticagrelor 31% 28%
Tolvaptan 30% 20%
Trimethoprim 22-28% NA
Digoxin concentrations increased, but magnitude is unclear
Alprazolam, azithromycin, cyclosporine, diclofenac, diphenoxylate, epoprostenol, esomeprazole, ibuprofen, ketoconazole, lansoprazole, metformin, omeprazole Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin concentrations decreased
Acarbose, activated charcoal, albuterol, antacids, certain cancer chemotherapy or radiation therapy, cholestyramine, colestipol, extenatide, kaolin-pectin, meals high in bran, metoclopramide, miglitol, neomycin, penicillamine, phenytoin, rifampin, St. John’s Wort, sucralfate and sulfasalazine Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20-40% as necessary.


Table name:
Bleeding times
Clinical Impact: Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention: This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact: The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention: Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact: Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention: This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.


Table name:
Calcium Channel Blockers Antifungals Antibiotics Glucocorticoids Other Drugs
diltiazem fluconazole azithromycin methylprednisolone Allopurinol
nicardipine itraconazole clarithromycin   Amiodarone
verapamil ketoconazole erythromycin   Bromocriptine
  voriconazole quinupristin/ dalfopristin   colchicine
        danazol
        imatinib
        metoclopramide
        nefazodone
        oral contraceptives


Table name:
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
1   = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
2   = Is not administered but is an active metabolite of carbamazepine.
NC=Less than 10% change in plasma concentration
NE=Not Evaluated
AED Coadministered AED Concentration Topiramate Concentration
Phenytoin NC or 25% increase 1 48% decrease
Carbamazepine (CBZ) NC 40% decrease
CBZ epoxide 2 NC NE
Valproic acid 11% decrease 14% decrease
Phenobarbital NC NE
Primidone NC NE
Lamotrigine NC at TPM doses up to 400 mg/day 13% decrease


Table name:
Drugs That May Increase the Risk of Hypoglycemia
Drugs: Antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, propoxyphene, salicylates, somatostatin analog (e.g., octreotide), and sulfonamide antibiotics.
Intervention: Dose adjustment and increased frequency of glucose monitoring may be required when NOVOLOG is co-administered with these drugs.
Drugs That May Decrease the Blood Glucose Lowering Effect of NOVOLOG
Drugs: Atypical antipsychotics (e.g., olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones.
Intervention: Dose adjustment and increased frequency of glucose monitoring may be required when NOVOLOG is co-administered with these drugs.
Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of NOVOLOG
Drugs: Alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia.
Intervention: Dose adjustment and increased frequency of glucose monitoring may be required when NOVOLOG is co-administered with these drugs.
Drugs That May Blunt Signs and Symptoms of Hypoglycemia
Drugs: Beta-blockers, clonidine, guanethidine and reserpine
Intervention: Increased frequency of glucose monitoring may be required when NOVOLOG is co-administered with these drugs.


Table name:
Concomitant Drug Name or Drug Class
Clinical Rationale
Clinical Recommendation

StrongCYP3A4Inhibitors (e.g.,itraconazole,clarithromycin) or strongCYP2D6inhibitors (e.g.,quinidine,fluoxetine,paroxetine) 
The concomitant use of aripiprazole tablets withstrong CYP3A4 orCYP2D6inhibitorsincreasedthe exposure ofaripiprazole tabletscomparedto the use of aripiprazole tabletsalone[seeCLINICALPHARMACOLOGY(12.3)].
Withconcomitant use of aripiprazole tablets with a strongCYP3A4inhibitororCYP2D6inhibitor, reducethearipiprazole tablets dosage[see DOSAGEANDADMINISTRATION(2.7)].
StrongCYP3A4Inducers (e.g.,carbamazepine,rifampin)
The concomitant use of aripiprazole tabletsandcarbamazepine decreased the exposure of aripiprazole tablets compared to the use of aripiprazole tablets alone [see CLINICALPHARMACOLOGY(12.3)].
Withconcomitant use of aripiprazole tablets with a strongCYP3A4inducer, consider increasing the aripiprazole tabletsdosage[see DOSAGE ANDADMINISTRATIO(2.7)].
AntihypertensiveDrugs
Duetoitsalphaadrenergicantagonism,aripiprazole tablets hasthepotentialtoenhance the effect of certainantihypertensive agents.
Monitor bloodpressureand adjustdoseaccordingly[seeWARNINGS AND PRECAUTIONS(5.7)].
Benzodiazepines(e.g., lorazepam)
Theintensityofsedationwas greaterwith the combination of oral aripiprazole tabletsandlorazepam as comparedtothat observedwith aripiprazole alone.Theorthostatichypotension observed wasgreaterwith the combination as comparedtothatobserved withlorazepamalone[seeWARNINGSANDPRECAUTIONS(5.7)]
Monitorsedation and blood pressure.Adjust dose accordingly.


Table name:
Coadministered Drug Dosing Schedule Effect on Active Moiety (Risperidone + 9- Hydroxy-Risperidone (Ratio*) Risperidone Dose Recommendation
Coadministered Drug Risperidone AUC Cmax
Enzyme (CYP2D6) Inhibitors        
Fluoxetine 20 mg/day 2 or 3 mg twice daily 1.4 1.5 Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine 10 mg/day 4 mg/day 1.3 - Re-evaluate dosing. Do not exceed 8 mg/day
20 mg/day 4 mg/day 1.6 -
40 mg/day 4 mg/day 1.8 -
Enzyme (CYP3A/PgP inducers) Inducers          
Carbamazepine 573 ± 168 mg/day 3 mg twice daily 0.51 0.55 Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors          
Ranitidine 150 mg twice daily 1 mg single dose 1.2 1.4 Dose adjustment not needed
Cimetidine 400 mg twice daily 1 mg single dose 1.1 1.3 Dose adjustment not needed
Erythromycin 500 mg four times daily 1 mg single dose 1.1 0.94 Dose adjustment not needed
           
Other Drugs          
Amitriptyline 50 mg twice daily 3 mg twice daily 1.2 1.1 Dose adjustment not needed


Table name:
Table 8: Selected Drug Interactions in Adults
Concomitant Drug Class:
Drug Name
Effect on Concentration of Raltegravir Clinical Comment
Metal-Containing Antacids
aluminum and/or magnesium-containing antacids Coadministration or staggered administration of aluminum and/or magnesium hydroxide-containing antacids and ISENTRESS is not recommended.
Other Agents
rifampin The recommended dosage of ISENTRESS is 800 mg twice daily during coadministration with rifampin. There are no data to guide co-administration of ISENTRESS with rifampin in patients below 18 years of age [see Dosage and Administration (2.1)].


Table name:
Interacting Drug
Interaction

Multivalent cation-containing products including antacids, metal cation or didanosine


Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. 




Warfarin
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)

Antidiabetic agent

Carefully monitor blood glucose (5.11, 7.3)


Table name:
Table 3: Clinically Significant Drug Interactions with Celecoxib
 Drugs That Interfere w ith Hemostasis
Clinical Impact:
Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of Celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:
Monitor patients with concomitant use of celecoxib with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11) ].
 Aspirin
Clinical Impact:
Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2) ].
In two studies in healthy volunteers, and in patients with osteoarthritis and established heart disease respectively, celecoxib (200 to 400 mg daily) has demonstrated a lack of interference with the cardioprotective antiplatelet effect of aspirin (100 to 325 mg).
Intervention:
Concomitant use of celecoxib and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11) ].
Celecoxib is not a substitute for low dose aspirin for cardiovascular protection.
 ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:
NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:
During concomitant use of celecoxib and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of celecoxib and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6) ]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
 Diuretics
Clinical Impact:
Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:
During concomitant use of celecoxib with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6) ].
 Digoxin
Clinical Impact:
The concomitant use of Celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:
During concomitant use of celecoxib and digoxin, monitor serum digoxin levels.
 Lithium
Clinical Impact:
NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:
During concomitant use of celecoxib and lithium, monitor patients for signs of lithium toxicity.
 Methotrexate
Clinical Impact:
Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Celecoxib has no effect on methotrexate pharmacokinetics.
Intervention:
During concomitant use of celecoxib and methotrexate, monitor patients for methotrexate toxicity.
 Cyclosporine
Clinical Impact:
Concomitant use of celecoxib and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:
During concomitant use of celecoxib and cyclosporine, monitor patients for signs of worsening renal function.
 NSAIDs a nd Salicylates
Clinical Impact:
Concomitant use of Celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2) ].
Intervention:
The concomitant use of Celecoxib with other NSAIDs or salicylates is not recommended.
 Pemetrexed
Clinical Impact:
Concomitant use of celecoxib and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:
During concomitant use of celecoxib and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.
NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.
In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
 CYP2C9 Inhibitors or inducers
Clinical Impact:
Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Co­-administration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of celecoxib.
Intervention
Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers. [see Clinical Pharmacology (12.3) ].
 CYP2D6 substrates
Clinical Impact:
In vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6 (e.g. atomoxetine), and celecoxib may enhance the exposure and toxicity of these drugs.
Intervention
Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2D6 substrates. [see Clinical Pharmacology (12.3) ].
 Corticosteroids
Clinical Impact:
Concomitant use of corticosteroids with celecoxib may increase the risk of GI ulceration or bleeding.
Intervention
Monitor patients with concomitant use of celecoxib with corticosteroids for signs of bleeding [see Warnings and Precautions (5.2) ].


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7.1, 7.2, 7.3, 7.4)
Interacting Agents Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone Avoid simvastatin
Gemfibrozil, cyclosporine, danazol Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil Do not exceed 20 mg simvastatin daily
Diltiazem Do not exceed 40 mg simvastatin daily
Grapefruit juice Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Table 2 Examples of CYP450 Interactions with Warfarin
 Enzyme
 Inhibitors
 Inducers
 CYP2C9 
 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast
 aprepitant, bosentan, carbamazepine, phenobarbital, rifampin 
 CYP1A2 
 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton
 montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking 
 CYP3A4 
 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton
 armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide 


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
 Concomitant  Drug
 Effect  on  Concentration  of  Lamotrigine  or 
Concomitant  Drug
 Clinical  Comment 
 ↓= Decreased (induces lamotrigine gluronidation).
↑= Increased (inhibits lamotrigine glucuronidation).
?= Conflicting data.
 Estrogen-containing oral 
contraceptive preparations 
containing 30 mcg ethinylestradiol 
and 150 mcg levonorgestrel
 ↓ lamotrigine




 Decreased lamotrigine levels 
approximately 50%.



 
 ↓ levonorgestrel
 Decrease in levonorgestrel component by 19%.
 Carbamazepine (CBZ) and 
CBZ epoxide
 ↓ lamotrigine

 Addition of carbamazepine decreases lamotrigine 
concentration approximately 40%.

 
 ? CBZ epoxide
 May increase CBZ epoxide levels
 Phenobarbital/Primidone
 ↓ lamotrigine
 Decreased lamotrigine 
concentration approximately 40%.
 Phenytoin (PHT)
 ↓ lamotrigine
 Decreased lamotrigine 
concentration approximately 40%
 Rifampin
 ↓ lamotrigine
 Decreased lamotrigine AUC 
approximately 40%
 Valproate
 ↑ lamotrigine

 Increased lamotrigine concentrations slightly 
more than 2-fold.

 
 ? valproate
 Decreased valproate concentrations an average of 
25% over a 3-week period then stabilized in healthy volunteers; 
no change in controlled clinical trials in epilepsy patients.



Table name:
Table 3: Drugs Affected by Phenytoin 
* The effect of phenytoin on phenobarbital, valproic acid and sodium valproate serum levels is unpredictable 
Interacting Agent
Examples
Drugs whose efficacy is impaired by phenytoin
Azoles
Fluconazole, ketoconazole, itraconazole, posaconazole, voriconazole
Antineoplastic agents
Irinotecan, paclitaxel, teniposide
Delavirdine
Phenytoin can substantially reduce the concentrations of delavirdine. This can lead to loss of virologic response and possible resistance [see Contraindications (4)].
Neuromuscular blocking agents
Cisatracurium, pancuronium, rocuronium and vecuronium: resistance to the neuromuscular blocking action of the nondepolarizing neuromuscular blocking agents has occurred in patients chronically administered phenytoin. Whether or not phenytoin has the same effect on other non-depolarizing agents is unknown.
Prevention or Management:   Patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected, and infusion rate requirements may be higher.
Warfarin
Increased and decreased PT/INR responses have been reported when phenytoin is coadministered with warfarin
Other
Corticosteroids, doxycycline, estrogens, furosemide, oral contraceptives, paroxetine, quinidine, rifampin, sertraline, theophylline, and vitamin D
Drugs whose level is decreased by phenytoin
Antiepileptic drugs*
Carbamazepine, felbamate, lamotrigine, topiramate, oxcarbazepine,
Antilipidemic agents
Atorvastatin, fluvastatin, simvastatin
Antiviral agents
Efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir Fosamprenavir: phenytoin when given with fosamprenavir alone may decrease the concentration of amprenavir, the active metabolite. Phenytoin when given with the combination of fosamprenavir and ritonavir may increase the concentration of amprenavir
Calcium channel blockers
Nifedipine, nimodipine, nisoldipine, verapamil
Other
Albendazole (decreases active metabolite), chlorpropamide, clozapine, cyclosporine, digoxin, folic acid, methadone, mexiletine, praziquantel, quetiapine


Table name:
Antibiotics     Anticonvulsants  Other Drugs/Dietary Supplements  
 nafcillin carbamazepine         bosentan
 rifampin  oxcarbazepine  octreotide
   phenobarbital  orlistat
   phenytoin  sulfinpyrazone
     terbinafine
     ticlopidine
     St. John's Wort


Table name:
Drugs that Affect Renal          
Function
A decline in GFR or tubular secretion, as from ACE inhibitors,          
angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs
[NSAIDs], COX-2 inhibitors may impair the excretion of digoxin.
Antiarrthymics Dofetilide Concomitant administration with digoxin was associated with a higher rate of torsades de pointes.
  Sotalol  Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
  Dronedarone Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone
Analog
Teriparatide Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement Thyroid Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics Epinephrine Norepinephrine Dopamine Can increase the risk of cardiac arrhythmias.
Neuromuscular Blocking
Agents
Succinylcholine May cause sudden extrusion of potassium from muscle cells, causing arrhythmias in patients taking digoxin.
Supplements Calcium If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers
and calcium channel
blockers
  Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.
Ivabradine Can increase the risk of bradycardia.


Table name:
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
Table 7:  Summary of AED Interactions with Oxcarbazepine
1nc denotes a mean change of less than 10%
2Pediatrics
3Mean increase in adults at high oxcarbazepine doses
AED
Coadministered
Dose of AED
(mg/day)
Oxcarbazepine Dose
(mg/day)
Influence of
Oxcarbazepine on AED
Concentration
(Mean Change,
90% Confidence
Interval)
Influence of
AED on MHD
Concentration
(Mean Change,
90% Confidence
Interval)
Carbamazepine
400 to 2000
900
nc 1
40% decrease
[CI: 17% decrease,
57% decrease]
Phenobarbital
100 to150
600 to 1800
14% increase
[CI: 2% increase,
24% increase]
25% decrease
[CI: 12% decrease,
51% decrease]
Phenytoin
250 to 500
600 to 1800
>1200 to 2400
nc 1,2
up to 40%
increase 3
[CI: 12% increase,
60% increase]
30% decrease
[CI: 3% decrease,
48% decrease]
Valproic acid
400 to 2800
600 to 1800
nc 1
18% decrease
[CI: 13% decrease,
40% decrease]
Lamotrigine
200
1200
nc 1
nc 1


Table name:
Table 5. Clinically-Significant Drug Interactions with Sertraline Hydrochloride
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:
The concomitant use of SSRIs including sertraline hydrochloride and MAOIs increases the risk of serotonin syndrome.
Intervention:
Sertraline hydrochloride is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [See Dosage and Administration (2.5), Contraindications (4), Warnings and Precautions (5.2)].
Examples:
selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue
Pimozide
Clinical Impact:
Increased plasma concentrations of pimozide, a drug with a narrow therapeutic index, may increase the risk of QT prolongation and ventricular arrhythmias.
Intervention:
Concomitant use of pimozide and sertraline hydrochloride is contraindicated [See Contraindications (4)].
Other Serotonergic Drugs
Clinical Impact:
The concomitant use of serotonergic drugs with sertraline hydrochloride increases the risk of serotonin syndrome.
Intervention:
Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of sertraline hydrochloride and/or concomitant serotonergic drugs [See Warnings and Precautions (5.2)].
Examples:
other SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort
Drugs that Interfere with Hemostasis (antiplatelet agents and anticoagulants)
Clinical Impact:
The concurrent use of an antiplatelet agent or anticoagulant with sertraline hydrochloride may potentiate the risk of bleeding.
Intervention:
Inform patients of the increased risk of bleeding associated with the concomitant use of sertraline hydrochloride and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio [See Warnings and Precautions (5.3)].
Examples:
aspirin, clopidogrel, heparin, warfarin
Drugs Highly Bound to Plasma Protein
Clinical Impact:
Sertraline hydrochloride is highly bound to plasma protein. The concomitant use of sertraline hydrochloride with another drug that is highly bound to plasma protein may increase free concentrations of sertraline hydrochloride or other tightly-bound drugs in plasma [See Clinical Pharmacology (12.3)] .
Intervention:
Monitor for adverse reactions and reduce dosage of sertraline hydrochloride or other protein-bound drugs as warranted.
Examples:
warfarin
Drugs Metabolized by CYP2D6
Clinical Impact:
Sertraline hydrochloride is a CYP2D6 inhibitor [See Clinical Pharmacology (12.3)] . The concomitant use of sertraline hydrochloride with a CYP2D6 substrate may increase the exposure of the CYP2D6 substrate.
Intervention:
Decrease the dosage of a CYP2D6 substrate if needed with concomitant sertraline hydrochloride use. Conversely, an increase in dosage of a CYP2D6 substrate may be needed if sertraline hydrochloride is discontinued.
Examples:
propafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, thoridazine, tolterodine, venlafaxine
Phenytoin
Clinical Impact:
Phenytoin is a narrow therapeutic index drug. Sertraline hydrochloride may increase phenytoin concentrations.
Intervention:
Monitor phenytoin levels when initiating or titrating sertraline hydrochloride. Reduce phenytoin dosage if needed.
Examples:
phenytoin, fosphenytoin


Table name:
Interacting DrugInteracting Drug InteractionInteraction
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products (2.4, 7.1)
Warfarin
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents
Carefully monitor blood glucose (5.12, 7.3)


Table name:
* The effect of phenytoin on phenobarbital, valproic acid and sodium valproate serum levels is unpredictable 
Interacting Agent
Examples
Drugs whose efficacy is impaired by phenytoin
Azoles
Fluconazole, ketoconazole, itraconazole, posaconazole, voriconazole
Antineoplastic agents
Irinotecan, paclitaxel, teniposide
Delavirdine
Phenytoin can substantially reduce the concentrations of delavirdine. This can lead to loss of virologic response and possible resistance [see Contraindications (4)].
Neuromuscular blocking agents
Cisatracurium, pancuronium, rocuronium and vecuronium: resistance to the neuromuscular blocking action of the nondepolarizing neuromuscular blocking agents has occurred in patients chronically administered phenytoin. Whether or not phenytoin has the same effect on other non-depolarizing agents is unknown.
Prevention or Management:   Patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected, and infusion rate requirements may be higher.
Warfarin
Increased and decreased PT/INR responses have been reported when phenytoin is coadministered with warfarin
Other
Corticosteroids, doxycycline, estrogens, furosemide, oral contraceptives, paroxetine, quinidine, rifampin, sertraline, theophylline, and vitamin D
Drugs whose level is decreased by phenytoin
Antiepileptic drugs*
Carbamazepine, felbamate, lamotrigine, topiramate, oxcarbazepine,
Antilipidemic agents
Atorvastatin, fluvastatin, simvastatin
Antiviral agents
Efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir Fosamprenavir: phenytoin when given with fosamprenavir alone may decrease the concentration of amprenavir, the active metabolite. Phenytoin when given with the combination of fosamprenavir and ritonavir may increase the concentration of amprenavir
Calcium channel blockers
Nifedipine, nimodipine, nisoldipine, verapamil
Other
Albendazole (decreases active metabolite), chlorpropamide, clozapine, cyclosporine, digoxin, folic acid, methadone, mexiletine, praziquantel, quetiapine


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine Decreased lamotrigine concentrations approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? carbamazepine epoxide May increase carbamazepine epoxide levels.
Lopinavir/ritonavir ↓ lamotrigine Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir ↓ lamotrigine Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine Increased lamotrigine concentrations slightly more than 2 fold.
? valproate There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.


Table name:
Table 6: Clinically Significant Drug Interactions with Paricalcitol
CYP3A Inhibitors
Clinical Impact Paricalcitol is partially metabolized by CYP3A. Hence, exposure of paricalcitol will increase upon coadministration with strong CYP3A inhibitors such as but not limited to: boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole.
Intervention Dose adjustment of paricalcitol capsules may be necessary. Monitor closely for iPTH and serum calcium concentrations, if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor.
Cholestyramine
Clinical Impact Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of paricalcitol.
Intervention Recommend to take paricalcitol capsules at least 1 hour before or 4 to 6 hours after taking cholestyramine (or at as great an interval as possible) to avoid impeding absorption of paricalcitol.
Mineral Oil
Clinical Impact Mineral oil or other substances that may affect absorption of fat may influence the absorption of paricalcitol.
Intervention Recommend to take paricalcitol capsules at least 1 hour before or 4 to 6 hours after taking mineral oil (or at as great an interval as possible) to avoid affecting absorption of paricalcitol.


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide

Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide






Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T and T levels and increase TSH, although all values remain within normal limits in most patients. 4 3
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate










Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
  Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration   Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen





Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid


Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)





Administration of these agents with levothyroxine results in an initial transient increase in FT . Continued administration results in a decrease in serum T and normal FT and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T and T to TBG and transthyretin. An initial increase in serum FT , is followed by return of FT to normal levels with sustained therapeutic serum salicylate concentrations, although total-T levels may decrease by as much as 30%. 4 4 4 4 3 4 4 4
  Drugs that may alter T 4 and T 3 metabolism
  Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin


Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. 4
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)




Administration of these enzyme inhibitors decrease the peripheral conversion of T to T , leading to decreased T levels. However, serum T levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T and T levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T concentrations by 30% with minimal change in serum T levels. However, long-term glucocorticoid therapy may result in slightly decreased T and T levels due to decreased TBG production (see above). 4 3 3 4 3 4 3 4 3 4
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives

Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)


Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin




Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2

Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin

Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of I, I, and Tc. 123 131 99m
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics









These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 3: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 10 and 20 mg in BPH patients on stable alpha-blocker therapy with tamsulosin 0.4 or 0.8 mg daily (Study 2)
Vardenafil 10 mg
Placebo-subtracted
Vardenafil 20 mg
Placebo-subtracted
Standing SBP -4 (-6.8, -0.3) -4 (-6.8, -1.4)
Supine SBP -5 (-8.2, -0.8) -4 (-6.3, -1.8)


Table name:
Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.*
*Refer to for information regarding table. PRECAUTIONS, Drug Interactions
albuterol,  systemic and inhaled felodipinefinasteride nizatidinenorfloxacin
amoxicillin hydrocortisone ofloxacin
ampicillin,   with or without sulbactam isoflurane isoniazid omeprazole prednisone, prednisolone
atenolol isradipine ranitidine
azithromycin influenza vaccine rifabutin
caffeine,   dietary ingestion ketoconazo lelomefloxacin roxithromycin sorbitol
cefaclor mebendazole         (purgative doses do not
co-trimoxazole  (trimethoprim and sulfamethoxazole) medroxyprogesteronemethylprednisolone    inhibit theophylline   absorption)
diltiazem metronidazole sucralfate
dirithromycin metoprolol terbutaline, systemic
enflurane nadolol terfenadine
famotidine nifedipine tetracycline
tocainide


Table name:
Table 3: Clinically Significant drug interactions with Celecoxib
Drugs  That  Interfere  with  Hemostasis
Clinical  Impact :
Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of Celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.
Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention :
Monitor patients with concomitant use of celecoxib capsules with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical  Impact :
Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)]. In two studies in healthy volunteers, and in patients with osteoarthritis and established heart disease respectively, celecoxib (200-400 mg daily) has demonstrated a lack of interference with the cardioprotective antiplatelet effect of aspirin (100-325 mg).
Intervention :
Concomitant use of celecoxib capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. Celecoxib capsules are not a substitute for low dose aspirin for cardiovascular protection.
ACE  Inhibitors Angiotensin  Receptor  Blockers and  Beta - Blockers
Clinical  Impact :
NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).
In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention :
During concomitant use of celecoxib capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of celecoxib capsules and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical  Impact :
Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention :
During concomitant use of celecoxib capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Digoxin
Clinical  Impact :
The concomitant use of Celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention :
During concomitant use of celecoxib capsules and digoxin, monitor serum digoxin levels.
Lithium
Clinical  Impact :
NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention :
During concomitant use of celecoxib capsules and lithium, monitor patients for signs of lithium toxicity. 
Methotrexate 
Clinical  Impact :
Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). 

Celecoxib has no effect on methotrexate pharmacokinetics. 
Intervention :
During concomitant use of celecoxib capsules and methotrexate, monitor patients for methotrexate toxicity. 
Cyclosporine 
Clinical  Impact :
Concomitant use of celecoxib capsules and cyclosporine may increase cyclosporine’s nephrotoxicity. 
Intervention :
During concomitant use of celecoxib capsules and cyclosporine, monitor patients for signs of worsening renal function. 
NSAIDs  and  Salicylates 
Clinical  Impact :
Concomitant use of Celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention :
The concomitant use of Celecoxib with other NSAIDs or salicylates is not recommended. 
Pemetrexed 
Clinical  Impact :
Concomitant use of celecoxib capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). 
Intervention :
During concomitant use of celecoxib capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. 

NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. 

In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. 
CYP2C9  Inhibitors  or  inducers 
Clinical  Impact :
Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Coadministration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of celecoxib. 
Intervention :
Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers. [see Clinical Pharmacology (12.3)].
CYP2D6  substrates 
Clinical  Impact :
In  vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is a potential for an in  vivo drug interaction with drugs that are metabolized by CYP2D6 (e.g. atomoxetine), and celecoxib may enhance the exposure and toxicity of these drugs. 
Intervention :
Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2D6 substrates. [see Clinical Pharmacology (12.3)].
Corticosteroids 
Clinical  Impact :
Concomitant use of corticosteroids with celecoxib capsules may increase the risk of GI ulceration or bleeding. 
Intervention :
Monitor patients with concomitant use of celecoxib capsules with corticosteroids for signs of bleeding [see Warnings and Precautions (5.2)].


Table name:
Interacting Drug Interaction
   Multivalent cation-containing products
   including antacids, metal cations or didanosine
   Absorption of levofloxacin is decreased when the tablet
   formulation  is taken within 2 hours of this product. (2.4, 7.1)
   Warfarin
   Effect may be enhanced. Monitor prothrombin time,
   INR, watch for bleeding (7.2)
   Antidiabetic agents
   Carefully monitor blood glucose (5.11, 7.3)


Table name:
Table 2. Drugs That May Decrease T4 Absorption (Hypothyroidism)
Potential impact: Concurrent use may reduce the efficacy of SYNTHROID by binding and delaying or preventing absorption, potentially resulting in hypothyroidism.
Drug or Drug Class Effect
Calcium Carbonate
Ferrous Sulfate
Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer SYNTHROID at least 4 hours apart from these agents.
Orlistat Monitor patients treated concomitantly with orlistat and SYNTHROID for changes in thyroid function.
Bile Acid Sequestrants
- Colesevelam
- Cholestyramine
- Colestipol
Ion Exchange Resins
- Kayexalate
- Sevelamer
Bile acid sequestrants and ion exchange resins are known to decrease levothyroxine absorption. Administer SYNTHROID at least 4 hours prior to these drugs or monitor TSH levels.
Other drugs:
Proton Pump Inhibitors
Sucralfate
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Gastric acidity is an essential requirement for adequate absorption of levothyroxine. Sucralfate, antacids and proton pump inhibitors may cause hypochlorhydria, affect intragastric pH, and reduce levothyroxine absorption. Monitor patients appropriately.


Table name:
Table 5. Food and Beverages to Avoid and Those which are Acceptable [see References (15)]
Class of Food and Beverage Tyramine-Rich Foods and Beverages to Avoid Acceptable Foods and Drinks, Containing No or Little Tyramine
Meat, Poultry, and Fish Air dried, aged and fermented meats, sausages and salamis (including cacciatore, hard salami and mortadella); pickled herring; and any spoiled or improperly stored meat, poultry, and fish (e.g., foods that have undergone changes in coloration, odor, or become moldy); spoiled or improperly stored animal livers Fresh meat, poultry, and fish, including fresh processed meats (e.g., lunch meats, hot dogs, breakfast sausage,
and cooked sliced ham)
Vegetables Broad bean pods (fava bean pods) All other vegetables
Dairy Aged cheeses Processed cheeses, mozzarella, ricotta cheese, cottage cheese, and yogurt
Beverages All varieties of tap beer and beers that have not been pasteurized so as to allow for ongoing fermentation Concomitant use of alcohol with EMSAM is not recommended. (Bottled and canned beers and wines contain little or no tyramine.)
Miscellaneous Concentrated yeast extract (e.g., Marmite), sauerkraut, most soybean products (including soy sauce and tofu), OTC supplements containing tyramine Brewer’s yeast, baker’s yeast, soy milk, commercial chain restaurant pizzas prepared with cheeses low in tyramine


Table name:
Concomitant Drug Name or Drug Class
Clinical Rationale
Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) 
The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].
With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)
The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].
With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Antihypertensive Drugs
Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.
Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.8)]. 


Table name:
AED Co-administered AED Concentration Topiramate Concentration
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated
Phenytoin NC or 25% increase = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. 48% decrease
Carbamazepine (CBZ) NC 40% decrease
CBZ epoxide = Is not administered but is an active metabolite of carbamazepine. NC NE
Valproic acid 11% decrease 14% decrease
Phenobarbital NC NE
Primidone NC NE
Lamotrigine NC at TPM doses up to 400 mg/day 13% decrease


Table name:
Table 8: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s) Recommendation Comments
Tizanidine Contraindicated Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)]
Theophylline Avoid Use
(Plasma Exposure Likely to be Increased and Prolonged)
Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions (5.9)].
Drugs Known to Prolong QT Interval Avoid Use Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.11) and Use in Specific Populations (8.5)].
Oral antidiabetic drugs Use with caution
Glucose-lowering effect potentiated
Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs [see Adverse Reactions (6.1)].
Phenytoin Use with caution
Altered serum levels of phenytoin (increased and decreased)
To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin with phenytoin.
Cyclosporine Use with caution
(transient elevations in serum creatinine)
Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs Use with caution
(Increase in anticoagulant effect)
The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate Use with caution
Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels
Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole Use with caution Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin [see Warnings and Precautions (5.15)].
Clozapine Use with caution Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs Use with caution Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil Use with caution
Two-fold increase in exposure
Monitor for sildenafil toxicity [see Clinical Pharmacology (12.3)].
Duloxetine Avoid Use
Five-fold increase in duloxetine exposure
If unavoidable, monitor for duloxetine toxicity.
Caffeine/Xanthine Derivatives Use with caution
Reduced clearance resulting in elevated levels and prolongation of serum half-life
Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Probenecid Use with caution
(interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)
Potentiation of ciprofloxacin toxicity may occur.


Table name:
Drugs that Affect Renal          
Function
 A decline in GFR or tubular secretion, as from ACE inhibitors,          
angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs
[NSAIDs], COX-2 inhibitors may impair the excretion of digoxin.
Antiarrthymics  Dofetilide  Concomitant administration with digoxin was associated with a higher rate of torsades de pointes.
    Sotalol   Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
    Dronedarone  Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone
Analog
 Teriparatide  Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement  Thyroid  Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics  Epinephrine Norepinephrine Dopamine  Can increase the risk of cardiac arrhythmias.
Neuromuscular Blocking
Agents
 Succinylcholine  May cause sudden extrusion of potassium from muscle cells, causing arrhythmias in patients taking digoxin.
Supplements  Calcium  If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers
and calcium channel
blockers
    Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.
Ivabradine Can increase the risk of bradycardia.


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
↓ = Decreased (induces lamotrigine glucuronidation).
↑ = Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
Concomitant Drug 
Effect on Concentration of 
Lamotrigine or Concomitant Drug 
Clinical Comment 
Estrogen-containing oral 
contraceptive 
preparations containing 30 mcg 
ethinylestradiol and 150 mcg levonorgestrel 
↓ lamotrigine 

↓ levonorgestrel 
Decreased lamotrigine concentrations approximately 50%. 

Decrease in levonorgestrel component by 19%. 
Carbamazepine and carbamazepine epoxide 
↓ lamotrigine 


? carbamazepine epoxide 
Addition of carbamazepine decreases 
lamotrigine concentration approximately 40%. 
May increase carbamazepine epoxide levels. 
Lopinavir/ritonavir 
↓ lamotrigine 
Decreased lamotrigine concentration approximately 50%. 
Atazanavir/ritonavir 
↓ lamotrigine
Decreased lamotrigine AUC approximately 32%. 
Phenobarbital/Primidone 
↓ lamotrigine 
Decreased lamotrigine concentration
 approximately 40%. 
Phenytoin 
↓ lamotrigine 
Decreased lamotrigine concentration 
approximately 40%. 
Rifampin 
↓ lamotrigine 
Decreased lamotrigine AUC 
approximately 40%. 
Valproate 
↑ lamotrigine

 ? valproate 
Increased lamotrigine concentrations 
slightly more than 2-fold. 
There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.


Table name:
Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
* Change relative to reference
Coadministered Drug
Dosing Schedule
Effect on Active
Moiety (Risperidone + 9-
Hydroxy- Risperidone (Ratio*)
Risperidone Dose
Recommendation

Coadministered Drug
Risperidone
AUC
Cmax

Enzyme (CYP2D6)
Inhibitors





Fluoxetine
20 mg/day 
2 or 3 mg twice
daily
1.4 
1.5
Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine
10 mg/day 
4 mg/day
1.3
-
Re-evaluate dosing. 

20 mg/day 
4 mg/day
1.6
-
Do not exceed 8 mg/day

40 mg/day 
4 mg/day
1.8
-

Enzyme (CYP3A/ PgP inducers) Inducers





Carbamazepine 
573 ± 168 mg/day
3 mg twice daily
0.51 
0.55
Titrate dose upwards.
Do not exceed twice the patient’s usual dose
Enzyme (CYP3A)
Inhibitors





Ranitidine 
150 mg twice daily
1 mg single dose
1.2 
1.4
Dose adjustment not
needed
Cimetidine 
400 mg twice daily
1 mg single dose
1.1 
1.3
Dose adjustment not
needed
Erythromycin 

500 mg four times
daily
1 mg single dose
1.1 
0.94
Dose adjustment not
needed






Other Drugs





Amitriptyline 
50 mg twice daily
3 mg twice daily
1.2 
1.1
Dose adjustment not
needed


Table name:
Concomitant Drug Name or Drug Class Clinical Rationale and Magnitude of Drug Interaction Clinical Recommendation
Strong and moderate CYP3A4 inhibitors, e.g., ketoconazole, fluconazole Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected resulting in an increase in exposure Consider dose reduction [see Dosage and Administration ( 2.7 )]
Strong and moderate CYP3A4 inducers, e.g., rifampin, efavirenz Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected resulting in a decrease in exposure Consider dose increase [see Dosage and Administration ( 2.7 )]


Table name:
Table 1: Clinically Significant Drug Interactions with Naproxen
Drugs That Interfere with Hemostasis
Clinical Impact: Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of naproxen tablets with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: Concomitant use of naproxen tablets and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding ( see WARNINGS; Hematologic Toxicity). Naproxen tablets are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: During concomitant use of naproxen tablets and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of naproxen tablets and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention During concomitant use of naproxen tablets with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact: The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of naproxen tablets and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen tablets and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of naproxen tablets and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of naproxen tablets and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of naproxen tablets and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of naproxen tablets and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of naproxen tablets and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact: Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention: Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen tablets are not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen tablets are not recommended.
Cholestyramine
Clinical Impact: Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention: Concomitant administration of cholestyramine with naproxen tablets are not recommended.
Probenecid
Clinical Impact: Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention: Patients simultaneously receiving naproxen tablets and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact: Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention: Patients simultaneously receiving naproxen tablets and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium ( 2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( 7.2)
Antidiabetic agents Carefully monitor blood glucose ( 5.11, 7.3)


Table name:
Table 2Clinically Significant Drug Interactions with Indomethacin Drugs That Interfere with Hemostasis
Clinical Impact: 
Indomethacin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant uses of indomethacin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. 
Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. 
Intervention: 
Monitor patients with concomitant use of indomethacin capsules with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact: 

Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)]. 
Intervention: 

Concomitant use of indomethacin capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. Indomethacin capsules are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: 

NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). 
In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. 
Intervention:
During concomitant use of indomethacin capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. 
During concomitant use of Indomethacin capsules and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)].
When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. 
Diuretics
Clinical Impact: 

Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. 
It has been reported that the addition of triamterene to a maintenance schedule of Indomethacin capsules resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin capsules and triamterene should not be administered together. 
Both Indomethacin capsules and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin capsules and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently. 
Intervention: 

Indomethacin and triamterene should not be administered together. During concomitant use of indomethacin capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects. 
Be aware that indomethacin and potassium-sparing diuretics may both be associated with increased serum potassium levels [see Warnings and Precautions (5.6)]. 
Digoxin
Clinical Impact: 

The concomitant use of indomethacin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. 
Intervention: 

During concomitant use of indomethacin capsules and digoxin, monitor serum digoxin levels. 
Lithium
Clinical Impact: 

NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearanceThe mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: 

During concomitant use of indomethacin capsules and lithium, monitor patients for signs of lithium toxicity. 
Methotrexate
Clinical Impact: 

Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). 
Intervention: 

During concomitant use of indomethacin capsules and methotrexate, monitor patients for methotrexate toxicity. 
Cyclosporine
Clinical Impact: 

Concomitant use of indomethacin capsules and cyclosporine may increase cyclosporine’s nephrotoxicity. 
Intervention: 

During concomitant use of indomethacin capsules and cyclosporine, monitor patients for signs of worsening renal function. 
NSAIDs and Salicylates
Clinical Impact: 

Concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)]. 
Combined use with diflunisal may be particularly hazardous because diflunisal causes significantly higher plasma levels of indomethacin. [see Clinical Pharmacology (12.3)]. 
In some patients, combined use of indomethacin and diflunisal has been associated with fatal gastrointestinal hemorrhage. 
Intervention: 

The concomitant use of indomethacin with other NSAIDs or salicylates, especially diflunisal, is not recommended. 
Pemetrexed
Clinical Impact: 

Concomitant use of indomethacin capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). 
Intervention: 

During concomitant use of indomethacin capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. 
NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. 
In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. 
Probenecid
Clinical Impact: 

When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased. 
Intervention: 

During the concomitant use of indomethacin capsules and probenecid, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect. When increases in the dose of indomethacin are made, they should be made carefully and in small increments. 


Table name:
Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme
Inhibitors
Inducers
CYP2C9 
amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast
aprepitant, bosentan, carbamazepine, phenobarbital, rifampin 
CYP1A2 
acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton
montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking 
CYP3A4 
alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton
armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide 


Table name:
Table 2: Clinically Significant Drug Interactions with mefenamic acid
Drugs That Interfere with Hemostasis
Clinical Impact: Mefenamic acid and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of mefenamic acid and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of PONSTEL with anticoagulants (e.g.,warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: Concomitant use of PONSTEL and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity).
PONSTEL is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: During concomitant use of PONSTEL and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of PONSTEL and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention During concomitant use of PONSTEL with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact: The concomitant use of mefenamic acid with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of PONSTEL and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of PONSTEL and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of PONSTEL and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of PONSTEL and cyclosporine may increase cyclosporine's nephrotoxicity.
Intervention: During concomitant use of PONSTEL and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of mefenamic acid with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: The concomitant use of mefenamic acid with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of PONSTEL and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of PONSTEL and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.
NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.
In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacid
Clinical Impact: In a single dose study (n=6), ingestion of an antacid containing 1.7-gram of magnesium hydroxide with 500-mg of mefenamic acid increased the Cmax and AUC of mefenamic acid by 125% and 36%, respectively.
Intervention: Concomitant use of mefenamic acid and antacids is not generally recommended because of possible increased adverse events .


Table name:
Interacting Drug
Interaction
Theophylline
Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin
Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents
Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin
Monitor phenytoin level (7)
Methotrexate
Monitor for methotrexate toxicity (7)
Cyclosporine
May increase serum creatinine. Monitor serum creatinine (7)
Multivalent cation-containing products including antacids, metal cations or didanosine
Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin (7)


Table name: Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents Prescribing Recommendations
 
Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Grapefruit juice Avoid grapefruit juice


Table name:
Table 18. Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug Dosing Schedule Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (RatioChange relative to reference) Risperidone Dose Recommendation
Coadministered Drug Risperidone AUC Cmax
Enzyme (CYP2D6) Inhibitors
Fluoxetine 20 mg/day 2 or 3 mg twice daily 1.4 1.5 Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine 10 mg/day 4 mg/day 1.3 - Re-evaluate dosing. Do not exceed 8 mg/day
20 mg/day 4 mg/day 1.6 -
40 mg/day 4 mg/day 1.8 -
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine 573 ± 168 mg/day 3 mg twice daily 0.51 0.55 Titrate dose upwards. Do not exceed twice the patient's usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine 150 mg twice daily 1 mg single dose 1.2 1.4 Dose adjustment not needed
Cimetidine 400 mg twice daily 1 mg single dose 1.1 1.3 Dose adjustment not needed
Erythromycin 500 mg four times daily 1 mg single dose 1.1 0.94 Dose adjustment not needed
Other Drugs
Amitriptyline 50 mg twice daily 3 mg twice daily 1.2 1.1 Dose adjustment not needed


Table name:
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine Decreased lamotrigine concentrations approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? carbamazepine epoxide May increase carbamazepine epoxide levels.
Lopinavir/ritonavir ↓ lamotrigine Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir ↓ lamotrigine Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine Increased lamotrigine concentrations slightly more than 2-fold.
? valproate There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.


Table name:
Table 13 Established and Other Potentially Significant Drug Interactions
Concomitant Drug
Effect on Concentration of Lamotrigine or Concomitant Drug
Clinical Comment
↓ = Decreased (induces lamotrigine glucuronidation)
↑ = Increased (inhibits lamotrigine glucuronidation)
? = Conflicting data
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel
↓ lamotrigine
Decreased lamotrigine concentrations approximately 50%
↓ levonorgestrel
Decrease in levonorgestrel component by 19%
Carbamazepine and Carbamazepine
epoxide
↓ lamotrigine
Addition of carbamazepine decreases lamotrigine concentration approximately 40%
? Carbamazepine
epoxide
May increase carbamazepine epoxide levels.
Lopinavir/ritonavir
↓ lamotrigine
Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir
↓ lamotrigine
Decreased lamotrigine AUC approximately 32%.
Phenobarbital/Primidone
↓ lamotrigine
Decreased lamotrigine concentration approximately 40%
Phenytoin
↓ lamotrigine
Decreased lamotrigine concentration approximately 40%
Rifampin
↓ lamotrigine
Decreased lamotrigine AUC approximately 40%
Valproate
↑ lamotrigine
Increased lamotrigine concentrations slightly more than 2-fold
? valproate
There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.


Table name: Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol
Drug Interactions Associated with Increased Risk of  Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents Prescribing Recommendations
 
Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice Avoid grapefruit juice


Table name:
Drugs That Interfere with Hemostasis
Clinical Impact: Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of diclofenac sodium and misoprostol with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].
Intervention: Concomitant use of diclofenac sodium and misoprostol and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. Diclofenac sodium and misoprostol is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: The concomitant administration of these drugs should be done with caution. Patients should be adequately hydrated and the clinical need to monitor the renal function should be assessed at the beginning of the concomitant treatment and periodically thereafter. During concomitant use of diclofenac sodium and misoprostol and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of diclofenac sodium and misoprostol and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)].
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of diclofenac sodium and misoprostol with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Digoxin
Clinical Impact: The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of diclofenac sodium and misoprostol and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of diclofenac sodium and misoprostol and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of diclofenac sodium and misoprostol and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of diclofenac and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of diclofenac sodium and misoprostol and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention: The concomitant use of diclofenac sodium and misoprostol with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of diclofenac and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of diclofenac sodium and misoprostol and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids
Clinical Impact: Antacids reduce the bioavailability of misoprostol acid. Antacids may also delay absorption of diclofenac. Magnesium-containing antacids exacerbate misoprostol-associated diarrhea.
Intervention: Concomitant use of diclofenac sodium and misoprostol and magnesium-containing antacids is not recommended.
Corticosteroids
Clinical Impact: Concomitant use of corticosteroids with diclofenac may increase the risk of GI ulceration or bleeding.
Intervention Monitor patients with concomitant use of diclofenac sodium and misoprostol with corticosteroids for signs of bleeding [see Warnings and Precautions (5.2)].
CYP2C9 Inhibitors or Inducers
Clinical Impact: Diclofenac is metabolized by cytochrome P450 enzymes, predominantly by CYP2C9. Co-administration of diclofenac with CYP2C9 inhibitors (e.g. voriconazole) may enhance the exposure and toxicity of diclofenac [see Clinical Pharmacology (12.3)] whereas co-administration with CYP2C9 inducers (e.g., rifampin) may lead to compromised efficacy of diclofenac.
Intervention: CYP 2C9 inhibitors: When concomitant use of CYP2C9 inhibitors is necessary, the total daily dose of diclofenac should not exceed the lowest recommended dose of diclofenac sodium 50 mg and misoprostol 200 mcg twice daily [see Dosage and Administration (2)]. CYP2C9 inducers: A dosage adjustment may be warranted when diclofenac sodium and misoprostol is administered with CYP2C9 inducers. Administer the separate products of misoprostol and diclofenac if a higher dose of diclofenac is deemed necessary.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
DRUG DESCRIPTION OF INTERACTION
Heparin Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin treated patients.
Pyrazinamide Inhibits pyrazinamide-induced hyperuricemia.
Uricosuric Agents Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited.


Table name:
Interacting Drug
Interaction
Multivalent cation-containing products including : antacids, sucralfate, multivitamins
Decreased moxifloxacin hydrochloride absorption. Take moxifloxacin hydrochloride at least 4 hours before or 8 hours after these products. (2.2, 7.1, 12.3)
Warfarin
Anticoagulant effect enhanced. Monitor prothrombin time/INR, and bleeding. (6, 7.2, 12.3)
Class IA and Class III antiarrhythmics:
Proarrhythmic effect may be enhanced. Avoid concomitant use. (5.3, 7.4)
Antidiabetic agents
Carefully monitor blood glucose. (5.10, 7.3)


Table name: Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol) In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. During concomitant use of diclofenac sodium topical gel and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of diclofenac sodium topical gel and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Drugs That Interfere with Hemostasis
Clinical Impact:
Intervention: Monitor patients with concomitant use of diclofenac sodium topical gel with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].
Intervention: Concomitant use of diclofenac sodium topical gel and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. Diclofenac sodium topical gel is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:
Intervention:
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of diclofenac sodium topical gel with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Digoxin
Clinical Impact: The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of diclofenac sodium topical gel and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of diclofenac sodium topical gel and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of diclofenac sodium topical gel and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of diclofenac sodium topical gel and cyclosporine may increase cyclosporine's nephrotoxicity.
Intervention: During concomitant use of diclofenac sodium topical gel and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention: The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of diclofenac sodium topical gel and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of diclofenac sodium topical gel and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and Gl toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine / Dopamine Agonists Glucocorticoids Octreotide Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( > 1 µg/kg/min); Glucocorticoids (hydrocortisone > 100 mg/day or equivalent); Octreotide ( > 100 µg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T 4 and T 3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) Administration of these agents with levothyroxine results in an initial transient increase in FT 4. Continued administration results in a decrease in serum T 4 and normal FT 4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T 4 and T 3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT 4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T 4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T 4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5’-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone > 4 mg/day) Propylthiouracil (PTU) Administration of these enzyme inhibitors decreases the peripheral conversion of T 4 to T 3, leading to decreased T 3 levels. However, serum T 4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T 3 and T 4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T 3 concentrations by 30% with minimal change in serum T 4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T 3 and T 4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Growth Hormones - Somatrem - Somatropin Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline) Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.


Table name: Clinical RecommendationStrong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin)Increase plasma naloxegol concentrations and may increase the risk of adverse reactions [see Clinical Pharmacology (12.3) ]Use with strong CYP3A4 inhibitors is contraindicated [see Contraindications (4) ].Moderate CYP3A4 inhibitors (e.g., diltiazem, erythromycin, verapamil)Avoid use with moderate CYP3A4 inhibitors; if unavoidable, decrease the dosage of MOVANTIK to 12.5 mg once daily and monitor for adverse reactions [see Dosage and Administration (2.4) ].Weak CYP3A4 inhibitors (e.g., quinidine, cimetidine)Clinically significant increases in naloxegol concentrations are not expected. No dosage adjustments are necessary. Grapefruit or grapefruit juiceThe effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation dependent. Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain preparation was used (e.g., high dose, double strength) or as a “moderate CYP3A inhibitor” when another preparation was used (e.g., low dose, single strength).Can increase plasma naloxegol concentrations. Avoid consumption of grapefruit or grapefruit juice during treatment with MOVANTIK [see Dosage and Administration (2.1) ].CYP3A4 InducersStrong CYP3A4 inducers (e.g., rifampin, carbamazepine, St. John’s Wort)Significantly decrease plasma naloxegol concentrations and may decrease the efficacy of MOVANTIK [see Clinical Pharmacology (12.3) ].    Use with strong CYP3A4 inducers is not recommended.Other opioid antagonistsPotential for additive effect of opioid receptor antagonism and increased risk of opioid withdrawal.Avoid use of MOVANTIKwith another opioid antagonist.
Table 2. Effects of Other Drugs on MOVANTIK
Concomitant Agent Mechanism of Action
CYP3A4 Inhibitors
Other Drug Interactions


Table name:
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓lamotrigine Decreased lamotrigine levels approximately 50%.
↓levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? CBZ epoxide May increase CBZ epoxide levels
Phenobarbital/Primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT) ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine   Increased lamotrigine concentrations slightly more than 2-fold.
? valproate Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
Table 3: Drugs that Can Increase the Risk of Bleeding
  Drug Class   Specific Drugs
  Anticoagulants   argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
  Antiplatelet Agents   aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
  Nonsteroidal Anti-Inflammatory Agents   celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
  Serotonin Reuptake Inhibitors   citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
Table 18. Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
*Change relative to reference
Coadministered Drug

Dosing Schedule
Effect on Active Moiety
(Risperidone + 9- Hydroxy-
Risperidone (Ratio*)
Risperidone Dose
Recommendation
Coadministered Drug
Risperidone
AUC
Cmax
Enzyme (CYP2D6) inhibitors




Fluoxetine
20 mg/day
2 or 3 mg twice daily
1.4
1.5

Re-evaluate dosing.
Do not exceed 8 mg/day
Paroxetine
10 mg/day
4 mg/day
1.3
-

Re-evaluate dosing.
Do not exceed 8 mg/day
20 mg/day
4 mg/day
1.6
-
40 mg/day
4 mg/day
1.8
-
Enzyme (CYP3A/ PgP inducers) Inducers





Carbamazepine
573 ± 168 mg/day

3 mg twice daily

0.51

0.55


Titrate dose upwards.
Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) inhibitors





Ranitidine
150 mg twice daily
1 mg single dose
1.2
1.4
Dose adjustment not needed
Cimetidine
400 mg twice daily
1 mg single dose
1.1
1.3
Dose adjustment not needed
Erythromycin
500 mg four times daily
1 mg single dose
1.1
0.94
Dose adjustment not needed
Other Drugs





Amitriptyline
50 mg twice daily
3 mg twice daily
1.2
1.1
Dose adjustment not Needed


Table name:
Drugs That Interfere with Hemostasis
Clinical Impact: • Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of naproxen or naproxen sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: Concomitant use of naproxen or naproxen sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen or naproxen sodium is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE-inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: • During concomitant use of naproxen or naproxen sodium and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of naproxen or naproxen sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen or naproxen sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact: The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of naproxen or naproxen sodium and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen or naproxen sodium and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of naproxen or naproxen sodium and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of naproxen or naproxen sodium and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of naproxen or naproxen sodium and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of naproxen or naproxen sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of naproxen or naproxen sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact: Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention: Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen or naproxen sodium is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed release tablets are not recommended.
Cholestyramine
Clinical Impact: Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention: Concomitant administration of cholestyramine with naproxen or naproxen sodium is not recommended.
Probenecid
Clinical Impact: Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention: Patients simultaneously receiving naproxen or naproxen sodium and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact: Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention: Patients simultaneously receiving naproxen or naproxen sodium and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine / Dopamine Agonists Glucocorticoids Octreotide Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( > 1 µg/kg/min); Glucocorticoids (hydrocortisone > 100 mg/day or equivalent); Octreotide ( > 100 µg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T 4 and T 3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) Administration of these agents with levothyroxine results in an initial transient increase in FT 4. Continued administration results in a decrease in serum T 4 and normal FT 4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T 4 and T 3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT 4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T 4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T 4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5’-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone > 4 mg/day) Propylthiouracil (PTU) Administration of these enzyme inhibitors decreases the peripheral conversion of T 4 to T 3, leading to decreased T 3 levels. However, serum T 4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T 3 and T 4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T 3 concentrations by 30% with minimal change in serum T 4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T 3 and T 4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Growth Hormones - Somatrem - Somatropin Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline) Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.


Table name:
Table 3: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction [See Clinical Pharmacology (12.3)]
Concomitant Drug Class:
Drug Name
Effect on Concentration of Etravirine or Concomitant Drug Clinical Comment
↑ = increase, ↓ = decrease, ↔ = no change
HIV-Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
efavirenzThe interaction between INTELENCE® and the drug was evaluated in a clinical study. All other drug interactions shown are predicted.
nevirapine
↓ etravirine Combining two NNRTIs has not been shown to be beneficial. Concomitant use of INTELENCE® with efavirenz or nevirapine may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of INTELENCE®. INTELENCE® and other NNRTIs should not be co-administered.
delavirdine ↑ etravirine Combining two NNRTIs has not been shown to be beneficial. INTELENCE® and delavirdine should not be co-administered.
HIV-Antiviral Agents: Protease Inhibitors (PIs)
atazanavir
(without ritonavir)
↓ atazanavir Concomitant use of INTELENCE® with atazanavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of atazanavir. INTELENCE® should not be co-administered with atazanavir without low-dose ritonavir.
atazanavir/ritonavir ↓ atazanavir
↑ etravirine
Concomitant use of INTELENCE® with atazanavir/ritonavir may cause a significant decrease in atazanavir Cmin and loss of therapeutic effect of atazanavir. In addition, the mean systemic exposure (AUC) of etravirine after co-administration of INTELENCE® with atazanavir/ritonavir is anticipated to be higher than the mean systemic exposure of etravirine observed in the Phase 3 trials after co-administration of INTELENCE® and darunavir/ritonavir (as part of the background regimen). INTELENCE® and atazanavir/ritonavir should not be co-administered.
darunavir/ritonavir ↓ etravirine The mean systemic exposure (AUC) of etravirine was reduced when INTELENCE® was co-administered with darunavir/ritonavir. Because all subjects in the Phase 3 trials received darunavir/ritonavir as part of the background regimen and etravirine exposures from these trials were determined to be safe and effective, INTELENCE® and darunavir/ritonavir can be co-administered without dose adjustments.
fosamprenavir
(without ritonavir)
↑ amprenavir Concomitant use of INTELENCE® with fosamprenavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of amprenavir. INTELENCE® should not be co-administered with fosamprenavir without low-dose ritonavir.
fosamprenavir/ritonavir ↑ amprenavir Due to a significant increase in the systemic exposure of amprenavir, the appropriate doses of the combination of INTELENCE® and fosamprenavir/ritonavir have not been established. INTELENCE® and fosamprenavir/ritonavir should not be co-administered.
indinavir
(without ritonavir)
↓ indinavir Concomitant use of INTELENCE® with indinavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of indinavir. INTELENCE® should not be co-administered with indinavir without low-dose ritonavir.
lopinavir/ritonavir ↓ etravirine The mean systemic exposure (AUC) of etravirine was reduced after co-administration of INTELENCE® with lopinavir/ritonavir (tablet). Because the reduction in the mean systemic exposures of etravirine in the presence of lopinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, INTELENCE® and lopinavir/ritonavir can be co-administered without dose adjustments.
nelfinavir
(without ritonavir)
↑ nelfinavir Concomitant use of INTELENCE® with nelfinavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of nelfinavir. INTELENCE® should not be co-administered with nelfinavir without low-dose ritonavir.
ritonavir ↓ etravirine Concomitant use of INTELENCE® with ritonavir 600 mg b.i.d. may cause a significant decrease in the plasma concentration of etravirine and loss of therapeutic effect of INTELENCE®. INTELENCE® and ritonavir 600 mg b.i.d. should not be co-administered.
saquinavir/ritonavir ↓ etravirine The mean systemic exposure (AUC) of etravirine was reduced when INTELENCE® was co-administered with saquinavir/ritonavir. Because the reduction in the mean systemic exposures of etravirine in the presence of saquinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, INTELENCE® and saquinavir/ritonavir can be co-administered without dose adjustments.
tipranavir/ritonavir ↓ etravirine Concomitant use of INTELENCE® with tipranavir/ritonavir may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of INTELENCE®. INTELENCE® and tipranavir/ritonavir should not be co-administered.
CCR5 Antagonists
maraviroc ↔ etravirine
↓ maraviroc
When INTELENCE® is co-administered with maraviroc in the absence of a potent CYP3A inhibitor (e.g., ritonavir boosted protease inhibitor), the recommended dose of maraviroc is 600 mg b.i.d. No dose adjustment of INTELENCE® is needed.
maraviroc/darunavir/ritonavir The reference for etravirine exposure is the pharmacokinetic parameters of etravirine in the presence of darunavir/ritonavir ↔ etravirine
↑ maraviroc
When INTELENCE® is co-administered with maraviroc in the presence of a potent CYP3A inhibitor (e.g., ritonavir boosted protease inhibitor), the recommended dose of maraviroc is 150 mg b.i.d. No dose adjustment of INTELENCE® is needed.
Other Agents
Antiarrhythmics:
digoxin
↔ etravirine
↑ digoxin
For patients who are initiating a combination of INTELENCE® and digoxin, the lowest dose of digoxin should initially be prescribed. For patients on a stable digoxin regimen and initiating INTELENCE®, no dose adjustment of either INTELENCE® or digoxin is needed. The serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect.
amiodarone,
bepridil,
disopyramide,
flecainide,
lidocaine (systemic),
mexiletine,
propafenone,
quinidine
↓ antiarrhythmics Concentrations of these antiarrhythmics may be decreased when co-administered with INTELENCE®. INTELENCE® and antiarrhythmics should be co-administered with caution. Drug concentration monitoring is recommended, if available.
Anticoagulants:
warfarin
↑ anticoagulants Warfarin concentrations may be increased when co-administered with INTELENCE®. The international normalized ratio (INR) should be monitored when warfarin is combined with INTELENCE®.
Anticonvulsants:
carbamazepine,
phenobarbital,
phenytoin
↓ etravirine Carbamazepine, phenobarbital and phenytoin are inducers of CYP450 enzymes. INTELENCE® should not be used in combination with carbamazepine, phenobarbital, or phenytoin as co-administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE®.
Antifungals:
fluconazole,
voriconazole
↑ etravirine
↔ fluconazole
↑ voriconazole
Co-administration of etravirine and fluconazole significantly increased etravirine exposures. The amount of safety data at these increased etravirine exposures is limited, therefore, etravirine and fluconazole should be co-administered with caution. No dose adjustment of INTELENCE® or fluconazole is needed.
Co-administration of etravirine and voriconazole significantly increased etravirine exposures. The amount of safety data at these increased etravirine exposures is limited, therefore, etravirine and voriconazole should be co-administered with caution. No dose adjustment of INTELENCE® or voriconazole is needed.
Antifungals:
itraconazole,
ketoconazole,
posaconazole
↑ etravirine
↓ itraconazole
↓ ketoconazole
↔ posaconazole
Posaconazole, a potent inhibitor of CYP3A4, may increase plasma concentrations of etravirine. Itraconazole and ketoconazole are potent inhibitors as well as substrates of CYP3A4. Concomitant systemic use of itraconazole or ketoconazole and INTELENCE® may increase plasma concentrations of etravirine. Simultaneously, plasma concentrations of itraconazole or ketoconazole may be decreased by INTELENCE®. Dose adjustments for itraconazole, ketoconazole or posaconazole may be necessary depending on the other co-administered drugs.
Antiinfectives:
clarithromycin
↑ etravirine
↓ clarithromycin
↑ 14-OH-clarithromycin
Clarithromycin exposure was decreased by INTELENCE®; however, concentrations of the active metabolite, 14-hydroxy-clarithromycin, were increased. Because 14-hydroxy-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered for the treatment of MAC.
Antimycobacterials:
rifampin,
rifapentine
↓ etravirine Rifampin and rifapentine are potent inducers of CYP450 enzymes. INTELENCE® should not be used with rifampin or rifapentine as co-administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE®.
Antimycobacterials:
rifabutin
↓ etravirine
↓ rifabutin
↓ 25-O-desacetylrifabutin
If INTELENCE® is NOT co-administered with a protease inhibitor/ritonavir, then rifabutin at a dose of 300 mg q.d. is recommended.
If INTELENCE® is co-administered with darunavir/ritonavir, lopinavir/ritonavir or saquinavir/ritonavir, then rifabutin should not be co-administered due to the potential for significant reductions in etravirine exposure.
Benzodiazepines:
diazepam
↑ diazepam Concomitant use of INTELENCE® with diazepam may increase plasma concentrations of diazepam. A decrease in diazepam dose may be needed.
Corticosteroids:
dexamethasone (systemic)
↓ etravirine Systemic dexamethasone induces CYP3A and can decrease etravirine plasma concentrations. This may result in loss of therapeutic effect of INTELENCE®. Systemic dexamethasone should be used with caution or alternatives should be considered, particularly for long-term use.
Herbal Products:
St. John's wort (Hypericum perforatum)
↓ etravirine Concomitant use of INTELENCE® with products containing St. John's wort may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE®. INTELENCE® and products containing St. John's wort should not be co-administered.
HMG-CoA
Reductase Inhibitors:
atorvastatin




fluvastatin,
lovastatin,
pravastatin,
rosuvastatin,
simvastatin
↔ etravirine
↓ atorvastatin
↑ 2-OH-atorvastatin




↔ etravirine
↑ fluvastatin,
↓ lovastatin,
↔ pravastatin,
↔ rosuvastatin,
↓ simvastatin
The combination of INTELENCE® and atorvastatin can be given without dose adjustments, however, the dose of atorvastatin may need to be altered based on clinical response.


No interaction between pravastatin, rosuvastatin and INTELENCE® is expected.

Lovastatin and simvastatin are CYP3A substrates and co-administration with INTELENCE® may result in lower plasma concentrations of the HMG-CoA reductase inhibitor. Fluvastatin is metabolized by CYP2C9 and co-administration with INTELENCE® may result in higher plasma concentrations of the HMG-CoA reductase inhibitor. Dose adjustments for these HMG-CoA reductase inhibitors may be necessary.
Immunosuppressants:
cyclosporine,
sirolimus,
tacrolimus
↓ immunosuppressant INTELENCE® and systemic immunosuppressants should be co-administered with caution because plasma concentrations of cyclosporine, sirolimus, or tacrolimus may be affected.
Narcotic Analgesics:
methadone
↔ etravirine
↔ methadone
INTELENCE® and methadone can be co-administered without dose adjustments, however, clinical monitoring for withdrawal symptoms is recommended as methadone maintenance therapy may need to be adjusted in some patients.
Phosphodiesterase Type 5
(PDE-5) Inhibitors:
sildenafil,
vardenafil,
tadalafil
↓ sildenafil
↓ N-desmethyl-sildenafil
INTELENCE® and sildenafil can be co-administered without dose adjustments, however, the dose of sildenafil may need to be altered based on clinical effect.
Platelet Aggregation Inhibitors:
clopidogrel
↓ clopidogrel (active) metabolite Activation of clopidogrel to its active metabolite may be decreased when clopidogrel is co-administered with INTELENCE®. Alternatives to clopidogrel should be considered.


Table name:
Interacting Drug 
Interaction 
Multivalent cation-containing products including antacids, metal cations or didanosine 
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin 
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents 
Carefully monitor blood glucose (5.11, 7.3)


Table name:
Table 5. Clinically-Significant Drug Interactions with Sertraline Hydrochloride
Monoamine  Oxidase  Inhibitors  ( MAOIs )
Clinical  Impact :
The concomitant use of SSRIs including sertraline hydrochloride and MAOIs increases the risk of serotonin syndrome.
Intervention :
Sertraline hydrochloride is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue  [ See  Dosage  and  Administration  ( 2 . 5 ),  Contraindications  ( 4 ),  Warnings  and  Precautions  ( 5 . 2)].
Examples :
selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue
Pimozide
Clinical  Impact :
Increased plasma concentrations of pimozide, a drug with a narrow therapeutic index, may increase the risk of QT prolongation and ventricular arrhythmias.
Intervention :
Concomitant use of pimozide and sertraline hydrochloride is contraindicated  [ See  Contraindications  ( 4)].
Other  Serotonergic  Drugs
Clinical  Impact :
The concomitant use of serotonergic drugs with sertraline hydrochloride increases the risk of serotonin syndrome.
Intervention :
Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of sertraline hydrochloride and/or concomitant serotonergic drugs  [ See  Warnings  and  Precautions  ( 5 . 2)].
Examples :
other SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort
Drugs  that  Interfere  with  Hemostasis  ( antiplatelet  agents  and  anticoagulants )
Clinical  Impact :
The concurrent use of an antiplatelet agent or anticoagulant with sertraline hydrochloride may potentiate the risk of bleeding.
Intervention :
Inform patients of the increased risk of bleeding associated with the concomitant use of sertraline hydrochloride and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio  [ See  Warnings  and  Precautions  ( 5 . 3)].
Examples :
aspirin, clopidogrel, heparin, warfarin
Drugs  Highly  Bound  to  Plasma  Protein
Clinical  Impact :
Sertraline hydrochloride is highly bound to plasma protein. The concomitant use of sertraline hydrochloride with another drug that is highly bound to plasma protein may increase free concentrations of sertraline hydrochloride or other tightly-bound drugs in plasma  [ See  Clinical  Pharmacology  ( 12 . 3 )].
Intervention :
Monitor for adverse reactions and reduce dosage of sertraline hydrochloride or other protein-bound drugs as warranted.
Examples :
warfarin
Drugs  Metabolized  by  CYP2D6
Clinical  Impact :
Sertraline hydrochloride is a CYP2D6 inhibitor  [ See  Clinical  Pharmacology  ( 12 . 3)]. The concomitant use of sertraline hydrochloride with a CYP2D6 substrate may increase the exposure of the CYP2D6 substrate.
Intervention :
Decrease the dosage of a CYP2D6 substrate if needed with concomitant sertraline hydrochloride use. Conversely, an increase in dosage of a CYP2D6 substrate may be needed if sertraline hydrochloride is discontinued.
Examples :
propafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, thoridazine, tolterodine, venlafaxine
Phenytoin
Clinical  Impact :
Phenytoin is a narrow therapeutic index drug. Sertraline hydrochloride may increase phenytoin concentrations.
Intervention :
Monitor phenytoin levels when initiating or titrating sertraline hydrochloride. Reduce phenytoin dosage if needed.
Examples :
phenytoin, fosphenytoin


Table name:
Factors Dosage Adjustments for Aripirazole Tablets
Known CYP2D6 Poor Metabolizers Administer half of usual dose
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors Administer half of usual dose
Strong CYP2D6 and CYP3A4 inhibitors Administer a quarter of usual dose
Strong CYP3A4 inducers Double usual dose over 1 to 2 weeks


Table name: Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology (12.3)]. Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see Clinical Pharmacology (12.3)]. There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole.
Table 3: Clinically Relevant Interactions Affecting Drugs Co-Administered with Omeprazole and Interaction with Diagnostics
Antiretrovirals
Clinical Impact:
The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known.
Intervention:
Rilpivirine-containing products: Concomitant use with omeprazole is contraindicated [see Contraindications (4)].
 
Atazanavir: Avoid concomitant use with omeprazole. See prescribing information for atazanavir for dosing information.
 
Nelfinavir: Avoid concomitant use with omeprazole. See prescribing information for nelfinavir.
 
Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities.
 
Other antiretrovirals: See prescribing information for specific antiretroviral drugs.
Warfarin
Clinical Impact:
Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
Intervention:
Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range.
Methotrexate
Clinical Impact:
Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions (5.11)].
Intervention:
A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate.
CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam)
Clopidogrel
Clinical Impact:
Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology (12.3)].
There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel.
Intervention:
Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy [see Warnings and Precautions (5.6)].
Citalopram
Clinical Impact:
Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology (12.3)].
Intervention:
Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.
Cilostazol
Clinical Impact:
Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology (12.3)].
Intervention:
Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.
Phenytoin
Clinical Impact:
Potential for increased exposure of phenytoin.
Intervention:
Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin.
Diazepam
Clinical Impact:
Increased exposure of diazepam [see Clinical Pharmacology (12.3)].
Intervention:
Monitor patients for increased sedation and reduce the dose of diazepam as needed.
Digoxin
Clinical Impact:
Potential for increased exposure of digoxin [see Clinical Pharmacology (12.3)].
Intervention:
Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)
Clinical Impact:
Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
Intervention:
Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF [see Clinical Pharmacology (12.3)].
 
See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact:
Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions.
Intervention:
See Contraindications, Warnings and Precautions  in prescribing information for clarithromycin.
 
See Drug Interactions in prescribing information for amoxicillin.
Tacrolimus
Clinical Impact:
Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.
Intervention:
Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact:
Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions (5.10), Clinical Pharmacology (12.2)].
Intervention:
Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
Interaction with Secretin Stimulation Test
Clinical Impact:
Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention:
Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology (12.2)].
False Positive Urine Tests for THC
Clinical Impact:
There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.
Intervention:
An alternative confirmatory method should be considered to verify positive results.
Other
Clinical Impact:
There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram).
Intervention:
Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole.


Table name:
Table 2: Clinically Significant Drug Interactions with Opana
Alcohol
Clinical Impact: The concomitant use of alcohol with OPANA can result in an increase of oxymorphone plasma levels and potentially fatal overdose of oxymorphone.
Intervention: Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products containing alcohol while on OPANA therapy [see Clinical Pharmacology (12.3)].
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines and other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [ Warnings and Precautions (5.4)].
Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue OPANA if serotonin syndrome is suspected.
Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)]. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
Intervention: The use of OPANA is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples: phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact: May reduce the analgesic effect of OPANA and/or precipitate withdrawal symptoms.
Intervention: Avoid concomitant use.
Examples: butorphanol, nalbuphine, pentazocine, buprenorphine,
Muscle Relaxants
Clinical Impact: Oxymorphone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of OPANA and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when OPANA is used concomitantly with anticholinergic drugs.
Anticholinergic Drugs
Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when OPANA is used concomitantly with anticholinergic drugs.
Cimetidine
Clinical Impact: Cimetidine can potentiate opioid-induced respiratory depression.
Intervention: Monitor patients for respiratory depression when OPANA and cimetidine are used concurrently.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
 Interacting Agents  Prescribing Recommendations
 Itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine, danazol  Contraindicated with simvastatin
 Amiodarone, verapamil, diltiazem  Do not exceed 10 mg simvastatin daily
 Amlodipine, ranolazine  Do not exceed 20 mg simvastatin daily
 Grapefruit juice  Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Table 7: Selected Drug Interactions in Adults
Concomitant Drug Class:
Drug Name
Effect on Concentration of Raltegravir Clinical Comment
HIV-1-Antiviral Agents
atazanavir Atazanavir, a strong inhibitor of UGT1A1, increases plasma concentrations of raltegravir. However, since concomitant use of ISENTRESS with atazanavir/ritonavir did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended.
atazanavir/ritonavir Atazanavir/ritonavir increases plasma concentrations of raltegravir. However, since concomitant use of ISENTRESS with atazanavir/ritonavir did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended.
efavirenz Efavirenz reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.
etravirine Etravirine reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.
tipranavir/ritonavir Tipranavir/ritonavir reduces plasma concentrations of raltegravir. However, since comparable efficacy was observed for this combination relative to other ISENTRESS-containing regimens in Phase 3 studies 018 and 019, no dose adjustment is recommended.
Other Agents
omeprazole Coadministration of medicinal products that increase gastric pH (e.g., omeprazole) may increase raltegravir levels based on increased raltegravir solubility at higher pH. However, since concomitant use of ISENTRESS with proton pump inhibitors and H2 blockers did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended.
rifampin Rifampin, a strong inducer of UGT1A1, reduces plasma concentrations of raltegravir. The recommended dosage of ISENTRESS is 800 mg twice daily during coadministration with rifampin.


Table name:
Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme Inhibitors Inducers
 CYP2C9  amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast  aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
 CYP1A2  acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton  montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
 CYP3A4  alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton  armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Table 4 Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table 5 for Magnitude of Interaction.
* The interaction between immediate-release VIRAMUNE and the drug was evaluated in a clinical study. The results of drug interaction studies with immediate-release VIRAMUNE are expected to also apply to VIRAMUNE XR.
Drug Name Effect on Concentration of
Nevirapine or Concomitant Drug
Clinical Comment
HIV Antiviral Agents: Protease Inhibitors (PIs)
Atazanavir/Ritonavir*

↓ Atazanavir
↑ Nevirapine

Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures.

Fosamprenavir*

↓ Amprenavir
↑ Nevirapine

Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.

Fosamprenavir/Ritonavir*

↓ Amprenavir

↑ Nevirapine

No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied.

Indinavir*

↓ Indinavir

The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established.

Lopinavir/Ritonavir*

↓Lopinavir

Dosing in adult patients:

A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.

Dosing in pediatric patients:

Please refer to the Kaletra® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.

Nelfinavir*

↓Nelfinavir M8 Metabolite
↓Nelfinavir Cmin

The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established.

Saquinavir/ritonavir

The interaction between nevirapine and saquinavir/ritonavir has not been evaluated

The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.

HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz*

↓ Efavirenz

The appropriate doses of these combinations with respect to safety and efficacy have not been established.

Delavirdine
Etravirine
Rilpivirine

  Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial.

Hepatitis C Antiviral Agents
Boceprevir

Plasma concentrations of boceprevir may be decreased due to induction of CYP3A4/5 by nevirapine.

Nevirapine and boceprevir should not be coadministered because decreases in boceprevir plasma concentrations may result in a reduction in efficacy.

Telaprevir

Plasma concentrations of telaprevir may be decreased due to induction of CYP3A4 by nevirapine and plasma concentrations of nevirapine may be increased due to inhibition of CYP3A4 by telaprevir.

Nevirapine and telaprevir should not be coadministered because changes in plasma concentrations of nevirapine, telaprevir, or both may result in a reduction in telaprevir efficacy or an increase in nevirapine-associated adverse events.

Other Agents
Analgesics:    
Methadone*

↓ Methadone

Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.

Antiarrhythmics:    
Amiodarone, disopyramide, lidocaine

Plasma concentrations may be decreased.

Appropriate doses for this combination have not been established.

Antibiotics:    
Clarithromycin*

↓ Clarithromycin
↑ 14-OH clarithromycin

Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.

Rifabutin*

↑ Rifabutin

Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.

Rifampin*

↓ Nevirapine

Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.

Anticonvulsants:
Carbamazepine, clonazepam, ethosuximide


Plasma concentrations of nevirapine and the anticonvulsant may be decreased.


Use with caution and monitor virologic response and levels of anticonvulsants.

Antifungals:    
Fluconazole*

↑Nevirapine

Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events.

Ketoconazole*

↓ Ketoconazole

Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.

Itraconazole

↓ Itraconazole

Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug.

Antithrombotics:
Warfarin


Plasma concentrations may be increased.


Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.

Calcium channel blockers:
Diltiazem, nifedipine, verapamil


Plasma concentrations may be decreased.


Appropriate doses for these combinations have not been established.

Cancer chemotherapy:
Cyclophosphamide


Plasma concentrations may be decreased.


Appropriate doses for this combination have not been established.

Ergot alkaloids:
Ergotamine


Plasma concentrations may be decreased.


Appropriate doses for this combination have not been established.

Immunosuppressants:
Cyclosporine, tacrolimus, sirolimus


Plasma concentrations may be decreased.


Appropriate doses for these combinations have not been established.

Motility agents:
Cisapride


Plasma concentrations may be decreased.


Appropriate doses for this combination have not been established.

Opiate agonists:
Fentanyl


Plasma concentrations may be decreased.


Appropriate doses for this combination have not been established.

Oral contraceptives:    
Ethinyl estradiol and Norethindrone*

↓ Ethinyl estradiol
↓ Norethindrone

Despite lower ethinyl estradiol and norethindrone exposures when coadministered with nevirapine, literature reports suggest that nevirapine has no effect on pregnancy rates among HIV-infected women on combined oral contraceptives. When coadministered with VIRAMUNE XR, no dose adjustment of ethinyl estradiol or norethindrone is needed when used in combination for contraception

When oral contraceptives are used for hormonal regulation during VIRAMUNE XR therapy, the therapeutic effect of the hormonal therapy should be monitored.


Table name:
Bleeding times
Clinical Impact: Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention: This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact: The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention: Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact: Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention: This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.


Table name:
Table 2. Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T4 and T3 serum transport - but FT4 concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors
(SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Drugs/Dietary Supplements That Decrease Cyclosporine Concentrations
Antibiotics nafcillin rifampin Anticonvulsants carbamazepine oxcarbazepine phenobarbital phenytoin Other Drugs / Dietary Supplements bosentan octreotide orlistat St. John’s Wort sulfinpyrazone terbinafine ticlopidine 


Table name:
Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name: Clinical ImpactSignificantly increased exposure of aprepitant may increase the risk of adverse reactions associated with aprepitant [see ADVERSE REACTIONS (6.1) and CLINICAL PHARMACOLOGY (12.3)].InterventionAvoid concomitant use of aprepitantExamplesModerate inhibitor: diltiazem Strong inhibitors: ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavirStrong CYP3A4 InducersClinical ImpactSubstantially decreased exposure of aprepitant in patients chronically taking a strong CYP3A4 inducer may decrease the efficacy of aprepitant [see CLINICAL PHARMACOLOGY (12.3)].InterventionAvoid concomitant use of aprepitantExamplesrifampin, carbamazepine, phenytoin
Moderate to Strong CYP3A4 Inhibitors
 
 
 
 
 
       
 
 
 
 
 
 
 


Table name:
Factors Dosage Adjustments for Aripiprazole
Known CYP2D6 Poor Metabolizers Administer half of usual dose
Known CYP2D6 Poor Metabolizersand strong CYP3A4 inhibitors Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors Administer half of usual dose
Strong CYP2D6 and CYP3A4inhibitors Administer a quarter of usual dose
Strong CYP3A4 inducers Double usual dose over 1 to 2 weeks


Table name:
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitors (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Table 18. Summary of Effect of Co-administered Drugs on Exposure to Active Moiety (Risperidone + 9- Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Co-administered Drug Dosing Schedule Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone) (RatioChange relative to reference) Risperidone Dose Recommendation

Co-administered Drug Risperidone AUC Cmax
Enzyme (CYP2D6) Inhibitors
Fluoxetine 20 mg/day 2 or 3 mg twice daily 1.4 1.5 Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine 10 mg/day 4 mg/day 1.3 - Re-evaluate dosing. Do not exceed 8 mg/day
20 mg/day 4 mg/day 1.6 -
40 mg/day 4 mg/day 1.8 -
Enzyme (CYP3A/PgP inducers) Inducers
Carbamazepine 573 ± 168 mg/day 3 mg twice daily 0.51 0.55 Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine 150 mg twice daily 1 mg single dose 1.2 1.4 Dose adjustment not needed
Cimetidine 400 mg twice daily 1 mg single dose 1.1 1.3 Dose adjustment not needed
Erythromycin 500 mg four times daily 1 mg single dose 1.1 0.94 Dose adjustment not needed
Other Drugs
Amitriptyline 50 mg twice daily 3 mg twice daily 1.2 1.1 Dose adjustment not needed


Table name:
a = Plasma concenrtration increased 25% in some patients, generally those on a twice a day dosing regimen
of phenytoin.
b = Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated
AED Co-administered
AED Concentration
Topiramate Concentration
Phenytoin
NC or 25% increase a
48% decrease
Carbamazepine (CBZ)
NC
40% decrease
CBZ epoxide b
NC
NE
Valproic acid
11% decrease
14% decrease
Phenobarbital
NC
NE
Primidone
NC
NE
Lamotrigine
NC at TPM doses up to 400 mg/day
13% decrease


Table name:
Drug Interactions Associated with Increased Risk of  Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice Avoid grapefruit juice


Table name:
Table 4 Established and Other Potentially SignificantThis table is not all inclusive. Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction
Concomitant Drug Class: Drug Name Effect on ConcentrationIncrease=↑; Decrease=↓; No Effect=↔ Clinical Comment
Antacids:
  antacids
  (e.g., aluminium, magnesium hydroxide, or calcium carbonate)
↔ rilpivirine
(antacids taken at least 2 hours before or at least 4 hours after rilpivirine)
↓ rilpivirine (concomitant intake)
The combination of COMPLERA and antacids should be used with caution as coadministration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). Antacids should only be administered either at least 2 hours before or at least 4 hours after COMPLERA.
Antimycobacterials:
  rifabutin
↓ rilpivirineThe interaction was evaluated in a clinical study. All other drug-drug interactions shown are predicted. Concomitant use of COMPLERA with rifabutin may cause significant decreases in rilpivirine plasma concentrations (induction of CYP3A enzymes). If COMPLERA is coadministered with rifabutin, an additional 25 mg tablet of rilpivirine (Edurant) once per day is recommended to be taken concomitantly with COMPLERA and with a meal for the duration of rifabutin coadministration.
Azole Antifungal Agents:
  fluconazole
  itraconazole
  ketoconazole
  posaconazole
  voriconazole
↑ rilpivirine , This interaction study has been performed with a dose higher than the recommended dose for rilpivirine. The dosing recommendation is applicable to the recommended dose of rilpivirine 25 mg once daily.
↓ ketoconazole ,
Concomitant use of COMPLERA with azole antifungal agents may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). No dose adjustment is required when COMPLERA is coadministered with azole antifungal agents. Clinically monitor for breakthrough fungal infections when azole antifungals are coadministered with COMPLERA.
Hepatitis C Antiviral Agents:
  ledipasvir/sofosbuvir
↑ tenofovir Patients receiving COMPLERA concomitantly with HARVONI™ (ledipasvir/sofosbuvir) should be monitored for adverse reactions associated with tenofovir disoproxil fumarate.
H2-Receptor Antagonists:
  cimetidine
  famotidine
  nizatidine
  ranitidine
↔ rilpivirine ,
(famotidine taken 12 hours before rilpivirine or 4 hours after rilpivirine)
↓ rilpivirine ,
(famotidine taken 2 hours before rilpivirine)
The combination of COMPLERA and H2-receptor antagonists should be used with caution as coadministration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). H2-receptor antagonists should only be administered at least 12 hours before or at least 4 hours after COMPLERA.
Macrolide or Ketolide Antibiotics:
  clarithromycin
  erythromycin
  telithromycin
↑ rilpivirine
↔ clarithromycin
↔ erythromycin
↔ telithromycin
Concomitant use of COMPLERA with clarithromycin, erythromycin, or telithromycin may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). Where possible, alternatives such as azithromycin should be considered.
Narcotic Analgesics:
  methadone
↓ R(–) methadone
↓ S(+) methadone
↔ rilpivirine
↔ methadone (when used with tenofovir)
No dose adjustments are required when initiating coadministration of methadone with COMPLERA. However, clinical monitoring is recommended as methadone maintenance therapy may need to be adjusted in some patients.


Table name:
Interacting Drug Interaction
Antacids, sucralfate, multivitamins, and other products containing multivalent cations Moxifloxacin absorption is decreased. Administer AVELOX Tablet at least 4 hours before or 8 hours after these products. (2.2, 7.1, 12.3, 17.2)
Warfarin Anticoagulant effect of warfarin may be enhanced. Monitor prothrombin time/INR, watch for bleeding. (6.4, 7.2, 12.3)
Class IA and Class III antiarrhythmics: Proarrhythmic effect may be enhanced. Avoid concomitant use. (5.3, 7.4)


Table name:
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine

↓ levonorgestrel
Decreased lamotrigine concentrations approximately 50%.
Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide ↓ lamotrigine


? carbamazepine epoxide
Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
May increase carbamazepine epoxide levels.
Lopinavir/ritonavir ↓ lamotrigine Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir ↓ lamotrigine Decreased lamotrigine AUC approximately 32%.
Phenobarbital/Primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine

? valproate
Increased lamotrigine concentrations slightly more than 2-fold.
There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.


Table name:
Drug Effect
 
Phenylephrine with prior administration of monoamine oxidase inhibitors (MAOI).
   
 Cardiac pressor response potentiated. May cause acute hypertensive crisis.
 
Phenylephrine with tricyclic anti-depressants.
   
 Pressor response increased.
 
Phenylephrine with ergot alkaloids.
   
 Excessive rise in blood pressure.
 
Phenylephrine with bronchodilator sympathomimetic agents and with epinephrine or other sympathomimetics.
    Tachycardia or other arrhythmias may occur.
 
Phenylephrine with prior administration of propranolol or other β-adrenergic blockers.
    Cardiostimulating effects blocked.
 
Phenylephrine with atropine sulfate.
   
 Reflex bradycardia blocked; pressor response enhanced.
 
Phenylephrine with prior administration of phentolamine or other α-adrenergic blockers.
    Pressor response decreased.
 
Phenylephrine with diet preparations, such as amphetamines or phenylpropanolamine.
    Synergistic adrenergic response.


Table name:
 Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.12, 7.3)


Table name:
Table 7: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction
Concomitant Drug Class: Drug Name Effect Clinical Comment
* The interaction between SUSTIVA and the drug was evaluated in a clinical study. All other drug interactions shown are predicted.
This table is not all-inclusive.
HIV antiviral agents
Protease inhibitor:
 Fosamprenavir
 calcium

↓ amprenavir
Fosamprenavir (unboosted): Appropriate doses of the combinations with respect to safety and efficacy have not been established.
Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when SUSTIVA is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when SUSTIVA is administered with fosamprenavir plus ritonavir twice daily.
Protease inhibitor:
 Atazanavir sulfate

↓ atazanavir*
Treatment-naive patients: When coadministered with SUSTIVA, the recommended dose of atazanavir is 400 mg with ritonavir 100 mg (together once daily with food) and SUSTIVA 600 mg (once daily on an empty stomach, preferably at bedtime).
Treatment-experienced patients: Coadministration of SUSTIVA and atazanavir is not recommended.
Protease inhibitor:
 Indinavir

↓ indinavir*
The optimal dose of indinavir, when given in combination with SUSTIVA, is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to SUSTIVA. When indinavir at an increased dose (1000 mg every 8 hours) was given with SUSTIVA (600 mg once daily), the indinavir AUC and Cmin were decreased on average by 33-46% and 39-57%, respectively, compared to when indinavir (800 mg every 8 hours) was given alone.
Protease inhibitor:
 Lopinavir/ritonavir

↓ lopinavir*
Lopinavir/ritonavir tablets should not be administered once daily in combination with SUSTIVA. In antiretroviral-naive patients, lopinavir/ritonavir tablets can be used twice daily in combination with SUSTIVA with no dose adjustment. A dose increase of lopinavir/ritonavir tablets to 600/150 mg (3 tablets) twice daily may be considered when used in combination with SUSTIVA in treatment-experienced patients where decreased susceptibility to lopinavir is clinically suspected (by treatment history or laboratory evidence). A dose increase of lopinavir/ritonavir oral solution to 533/133 mg (6.5 mL) twice daily taken with food is recommended when used in combination with SUSTIVA.
Protease inhibitor:
 Ritonavir

↑ ritonavir*
↑ efavirenz*
When ritonavir 500 mg q12h was coadministered with SUSTIVA 600 mg once daily, the combination was associated with a higher frequency of adverse clinical experiences (eg, dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when SUSTIVA is used in combination with ritonavir.
Protease inhibitor:
 Saquinavir

↓ saquinavir*
Should not be used as sole protease inhibitor in combination with SUSTIVA.
NNRTI:
 Other NNRTIs
↑ or ↓ efavirenz
and/or NNRTI
Combining two NNRTIs has not been shown to be beneficial. SUSTIVA should not be coadministered with other NNRTIs.
CCR5 co-receptor antagonist:
 Maraviroc

↓ maraviroc*
Refer to the full prescribing information for maraviroc for guidance on coadministration with efavirenz.
Integrase strand transfer inhibitor:
 Raltegravir

↓ raltegravir*
SUSTIVA reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.
Hepatitis C antiviral agents
Protease inhibitor:
 Boceprevir

↓ boceprevir*
Plasma trough concentrations of boceprevir were decreased when boceprevir was coadministered with SUSTIVA, which may result in loss of therapeutic effect. The combination should be avoided.
Protease inhibitor:
 Telaprevir

↓ telaprevir*
↓ efavirenz*
Concomitant administration of telaprevir and SUSTIVA resulted in reduced steady-state exposures to telaprevir and efavirenz.
Other agents
Anticoagulant:
 Warfarin

↑ or ↓ warfarin
Plasma concentrations and effects potentially increased or decreased by SUSTIVA.
Anticonvulsants:
 Carbamazepine

↓ carbamazepine*
↓ efavirenz*

There are insufficient data to make a dose recommendation for efavirenz. Alternative anticonvulsant treatment should be used.
 Phenytoin
 Phenobarbital
↓ anticonvulsant
↓ efavirenz
Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted.
Antidepressants:
 Bupropion

↓ bupropion*

The effect of efavirenz on bupropion exposure is thought to be due to the induction of bupropion metabolism. Increases in bupropion dosage should be guided by clinical response, but the maximum recommended dose of bupropion should not be exceeded.
 Sertraline ↓ sertraline* Increases in sertraline dosage should be guided by clinical response.
Antifungals:
 Voriconazole

↓ voriconazole*
↑ efavirenz*

SUSTIVA and voriconazole must not be coadministered at standard doses. Efavirenz significantly decreases voriconazole plasma concentrations, and coadministration may decrease the therapeutic effectiveness of voriconazole. Also, voriconazole significantly increases efavirenz plasma concentrations, which may increase the risk of SUSTIVA-associated side effects. When voriconazole is coadministered with SUSTIVA, voriconazole maintenance dose should be increased to 400 mg every 12 hours and SUSTIVA dose should be decreased to 300 mg once daily using the capsule formulation. SUSTIVA tablets should not be broken. [See Dosage and Administration (2.1) and Clinical Pharmacology (12.3, Tables 8 and 9) .]

 Itraconazole

↓ itraconazole*
↓ hydroxyitraconazole*

Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered.
 Ketoconazole ↓ ketoconazole Drug interaction studies with SUSTIVA and ketoconazole have not been conducted. SUSTIVA has the potential to decrease plasma concentrations of ketoconazole.
 Posaconazole ↓ posaconazole* Avoid concomitant use unless the benefit outweighs the risks.
Anti-infective:
 Clarithromycin

↓ clarithromycin*
↑ 14-OH metabolite*
Plasma concentrations decreased by SUSTIVA; clinical significance unknown. In uninfected volunteers, 46% developed rash while receiving SUSTIVA and clarithromycin. No dose adjustment of SUSTIVA is recommended when given with clarithromycin. Alternatives to clarithromycin, such as azithromycin, should be considered (see Other Drugs , following table). Other macrolide antibiotics, such as erythromycin, have not been studied in combination with SUSTIVA.
Antimycobacterials:
 Rifabutin

↓ rifabutin*
Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week.
 Rifampin ↓ efavirenz* If SUSTIVA is coadministered with rifampin to patients weighing 50 kg or more, an increase in the dose of SUSTIVA to 800 mg once daily is recommended.
Calcium channel blockers:
 Diltiazem

↓ diltiazem*
↓ desacetyl diltiazem*
↓ N-monodesmethyl diltiazem*
Diltiazem dose adjustments should be guided by clinical response (refer to the full prescribing information for diltiazem). No dose adjustment of efavirenz is necessary when administered with diltiazem.
Others (eg, felodipine, nicardipine, nifedipine, verapamil)
↓ calcium channel blocker
No data are available on the potential interactions of efavirenz with other calcium channel blockers that are substrates of CYP3A. The potential exists for reduction in plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response (refer to the full prescribing information for the calcium channel blocker).
HMG-CoA reductase inhibitors:
  Atorvastatin
  Pravastatin
  Simvastatin


  ↓ atorvastatin*
↓ pravastatin*
↓ simvastatin*
Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased. Consult the full prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose.
Hormonal contraceptives:
Oral
 Ethinyl estradiol/
 Norgestimate

↓ active metabolites
of norgestimate*

A reliable method of barrier contraception must be used in addition to hormonal contraceptives. Efavirenz had no effect on ethinyl estradiol concentrations, but progestin levels (norelgestromin and levonorgestrel) were markedly decreased. No effect of ethinyl estradiol/norgestimate on efavirenz plasma concentrations was observed.
Implant
 Etonogestrel

↓ etonogestrel

A reliable method of barrier contraception must be used in addition to hormonal contraceptives. The interaction between etonogestrel and efavirenz has not been studied. Decreased exposure of etonogestrel may be expected. There have been postmarketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients.
Immunosuppressants:
Cyclosporine, tacrolimus, sirolimus, and others metabolized by CYP3A

↓ immunosuppressant
Decreased exposure of the immunosuppressant may be expected due to CYP3A induction. These immunosuppressants are not anticipated to affect exposure of efavirenz. Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with efavirenz.
Narcotic analgesic:
 Methadone

↓ methadone*
Coadministration in HIV-infected individuals with a history of injection drug use resulted in decreased plasma levels of methadone and signs of opiate withdrawal. Methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms. Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms.


Table name:
Table 2. Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T4 and T3 serum transport - but FT4 concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors
(SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name: Clinical RecommendationStrong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin)Increase plasma naloxegol concentrations and may increase the risk of adverse reactions [see Clinical Pharmacology (12.3) ]Use with strong CYP3A4 inhibitors is contraindicated [see Contraindications (4) ].Moderate CYP3A4 inhibitors (e.g., diltiazem, erythromycin, verapamil)Avoid use with moderate CYP3A4 inhibitors; if unavoidable, decrease the dosage of MOVANTIK to 12.5 mg once daily and monitor for adverse reactions [see Dosage and Administration (2.4) ].Weak CYP3A4 inhibitors (e.g., quinidine, cimetidine)Clinically significant increases in naloxegol concentrations are not expected. No dosage adjustments are necessary. Grapefruit or grapefruit juiceThe effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation dependent. Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain preparation was used (e.g., high dose, double strength) or as a “moderate CYP3A inhibitor” when another preparation was used (e.g., low dose, single strength).Can increase plasma naloxegol concentrations. Avoid consumption of grapefruit or grapefruit juice during treatment with MOVANTIK [see Dosage and Administration (2.1) ].CYP3A4 InducersStrong CYP3A4 inducers (e.g., rifampin, carbamazepine, St. John’s Wort)Significantly decrease plasma naloxegol concentrations and may decrease the efficacy of MOVANTIK [see Clinical Pharmacology (12.3) ].    Use with strong CYP3A4 inducers is not recommended.Other opioid antagonistsPotential for additive effect of opioid receptor antagonism and increased risk of opioid withdrawal.Avoid use of MOVANTIKwith another opioid antagonist.
Table 2. Effects of Other Drugs on MOVANTIK
Concomitant Agent Mechanism of Action
 
CYP3A4 Inhibitors
 
Other Drug Interactions


Table name:
Drugs That Interfere with Hemostasis
Clinical Impact: • Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of naproxen or naproxen sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: Concomitant use of naproxen or naproxen sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen or naproxen sodium is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE-inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: • During concomitant use of naproxen or naproxen sodium and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of naproxen or naproxen sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen or naproxen sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact: The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of naproxen or naproxen sodium and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen or naproxen sodium and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of naproxen or naproxen sodium and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of naproxen or naproxen sodium and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of naproxen or naproxen sodium and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of naproxen or naproxen sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of naproxen or naproxen sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact: Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention: Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen or naproxen sodium is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed release tablets are not recommended.
Cholestyramine
Clinical Impact: Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention: Concomitant administration of cholestyramine with naproxen or naproxen sodium is not recommended.
Probenecid
Clinical Impact: Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention: Patients simultaneously receiving naproxen or naproxen sodium and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact: Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention: Patients simultaneously receiving naproxen or naproxen sodium and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.


Table name:
Name of the Concomitant Drug Change in the Concentration of Ganciclovir or Concomitant Drug Clinical Comment
 Zidovudine
↓ Ganciclovir
↑ Zidovudine
Zidovudine and valganciclovir hydrochloride each have the potential to cause neutropenia and anemia
 Probenecid
↑ Ganciclovir
Patients taking probenecid and valganciclovir hydrochloride should be monitored for evidence of ganciclovir toxicity
 Mycophenolate  Mofetil (MMF)
↔ Ganciclovir (in patients with normal renal function)
↔ MMF (in patients with normal renal function)
Patients with renal impairment should be monitored carefully as levels of MMF metabolites and ganciclovir may increase
 Didanosine
↓ Ganciclovir
↑ Didanosine
Patients should be closely monitored for didanosine toxicity


Table name:
Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s) Recommendation Comments
Tizanidine Contraindicated Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)].
Theophylline Avoid Use (Plasma Exposure Likely to be Increased and Prolonged) Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions (5.6).]
Drugs Known to Prolong QT Interval Avoid Use Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.10) and Use in Specific Populations (8.5)].
Oral antidiabetic drugs Use with caution Glucose-lowering effect potentiated Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported . Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs. [see Adverse Reactions (6.1).]
Phenytoin Use with caution Altered serum levels of phenytoin (increased and decreased) To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after coadministration of ciprofloxacin with phenytoin.
Cyclosporine Use with caution (transient elevations in serum creatinine) Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs Use with caution (Increase in anticoagulant effect) The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole Use with caution Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after coadministration with ciprofloxacin [see Warnings and Precautions (5.15)].
Clozapine Use with caution Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs Use with caution Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil Use with caution 2-fold increase in exposure Monitor for sildenafil toxicity (see Pharmacokinetics -(12.3)-] .
Duloxetine Avoid Use 5-fold increase in duloxetine exposure If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx ® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products) Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2)]. Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels) Potentiation of ciprofloxacin toxicity may occur.


Table name:
Table 2 Rifabutin Interaction Studies
Coadministered drug Dosing regimen of coadministered drug Dosing regimen of rifabutin Study population (n) Effect on rifabutin Effect on coadministered drug Recommendation
↑ indicates increase; ↓ indicates decrease; ↔ indicates no significant change
QD- once daily; BID- twice daily; TID – thrice daily
ND - No Data
AUC - Area under the Concentration vs. Time Curve; C max - Maximum serum concentration
ANTIVIRALS
Amprenavir 1200 mg BID × 10 days 300 mg QD × 10 days Healthy male subjects (6) ↑ AUC by 193%,
↑ Cmax by 119%
Reduce rifabutin dose by at least 50%. Monitor closely for adverse reactions.
Delavirdine 400 mg TID 300 mg QD HIV-infected patients (7) ↑ AUC by 230%,
↑ Cmax by 128%
↓ AUC by 80%,
↓ Cmax by 75%,
↓ Cmin by 17%
CONTRAINDICATED
Didanosine 167 or 250 mg BID × 12 days 300 or 600 mg QD × 1 HIV-infected patients (11)
Fosamprenavir/ ritonavir 700 mg BID plus ritonavir 100 mg BID × 2 weeks 150 mg every other day × 2 weeks Healthy subjects (15) ↔ AUC compared to rifabutin 300 mg QD alone
↓ Cmax by 15%
↑ AUC by 35% compared to historical control (fosamprenavir/ritonavir 700/100 mg BID),
↑ Cmax by 36%,
↑ Cmin by 36%,
Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with fosamprenavir/ritonavir combination.
Indinavir 800 mg TID × 10 days 300 mg QD × 10 days Healthy subjects (10) ↑ AUC by 173%,
↑ Cmax by 134%
↓ AUC by 34%,
↓ Cmax by 25%,
↓ Cmin by 39%
Reduce rifabutin dose by 50%, and increase indinavir dose from 800 mg to 1000 mg TID.
Lopinavir/ ritonavir 400/100 mg BID × 20 days 150 mg QD × 10 days Healthy subjects (14) ↑ AUC by 203% also taking zidovudine 500 mg QD
↓ Cmax by 112%
Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with lopinavir/ritonavir combination. Monitor closely for adverse reactions. Reduce rifabutin dosage further, as needed.
Saquinavir/ ritonavir 1000/100 mg BID × 14 or 22 days 150 mg every 3 days × 21–22 days Healthy subjects ↑ AUC by 53% compared to rifabutin 150 mg QD alone
↑ Cmax by 88%
(n=11)
↓ AUC by 13%,
↓ Cmax by 15%,
(n=19)
Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with saquinavir/ritonavir combination. Monitor closely for adverse reactions.
Ritonavir 500mg BID × 10 days 150 mg QD × 16 days Healthy subjects (5) ↑ AUC by 300%,
↑ Cmax by 150%
ND Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with lopinavir/ritonavir combination. Monitor closely for adverse reactions.
Reduce rifabutin dosage further, as needed.
Tipranavir/ ritonavir 500/200 BID × 15 doses 150 mg single dose Healthy subjects (20) ↑ AUC by 190%,
↑ Cmax by 70%
Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with tipranavir/ritonavir combination. Monitor closely for adverse reactions. Reduce rifabutin dosage further, as needed.
Nelfinavir 1250 mg BID × 7–8 days 150 mg QD × 8 days HIV-infected patients (11) ↑ AUC by 83%, compared to rifabutin 300 mg QD alone
↑ Cmax by 19%
Reduce rifabutin dose by 50% (to 150 mg QD) and increase the nelfinavir dose to 1250 mg BID
Zidovudine 100 or 200 mg q4h 300 or 450 mg QD HIV-infected patients (16) ↓ AUC by 32%,
↓ Cmax by 48%,
Because zidovudine levels remained within the therapeutic range during coadministration of rifabutin, dosage adjustments are not necessary.
ANTIFUNGALS
Fluconazole 200 mg QD × 2 weeks 300 mg QD × 2 weeks HIV-infected patients (12) ↑ AUC by 82%,
↑ Cmax by 88%
Monitor for rifabutin associated adverse events. Reduce rifabutin dose or suspend MYCOBUTIN use if toxicity is suspected.
Posaconazole 200 mg QD × 10 days 300 mg QD × 17 days Healthy subjects (8) ↑ AUC by 72%,
↑ Cmax by 31%
↓ AUC by 49%,
↓ Cmax by 43%
If co-administration of these two drugs cannot be avoided, patients should be monitored for adverse events associated with rifabutin administration, and lack of posaconazole efficacy.
Itraconazole 200 mg QD 300 mg QD HIV-Infected patients (6) data from a case report ↓ AUC by 70%,
↓ Cmax by 75%,
If co-administration of these two drugs cannot be avoided, patients should be monitored for adverse events associated with rifabutin administration, and lack of itraconazole efficacy. In a separate study, one case of uveitis was associated with increased serum rifabutin levels following co-administration of rifabutin (300 mg QD) with itraconazole (600–900 mg QD).
Voriconazole 400 mg BID × 7 days (maintenance dose) 300 mg QD × 7 days Healthy male subjects (12) ↑ AUC by 331%,
↑ Cmax by 195%
↑ AUC by ~100%,
↑ Cmax by ~100% compared to voriconazole 200 mg BID alone
CONTRAINDICATED
ANTI-PCP (Pneumocystis carinii pneumonia)
Dapsone 50 mg QD 300 mg QD HIV-infected patients (16) ND ↓ AUC by 27 –40%
Sulfamethoxazole- Trimethoprim 800/160 mg 300 mg QD HIV-infected patients (12) ↓ AUC by 15–20%
ANTI-MAC (Mycobacterium avium intracellulare complex)
Azithromycin 500 mg QD × 1 day, then 250 mg QD × 9 days 300 mg QD Healthy subjects (6)
Clarithromycin 500 mg BID 300 mg QD HIV-infected patients (12) ↑ AUC by 75% ↓ AUC by 50% Monitor for rifabutin associated adverse events. Reduce dose or suspend use of MYCOBUTIN if toxicity is suspected. Alternative treatment for clarithromycin should be considered when treating patients receiving rifabutin
ANTI-TB (Tuberculosis)
Ethambutol 1200 mg 300 mg QD × 7 days Healthy subjects (10) ND
Isoniazid 300 mg 300 mg QD × 7 days Healthy subjects (6) ND
OTHER
Methadone 20 – 100 mg QD 300 mg QD × 13 days HIV-infected patients (24) ND
Ethinylestradiol (EE)/Norethindrone (NE) 35 mg EE / 1 mg NE × 21 days 300 mg QD × 10 days Healthy female subjects (22) ND EE: ↓ AUC by
35%, ↓ C max by 20%
NE: ↓ AUC by 46%
Patients should be advised to use additional or alternative methods of contraception.
Theophylline 5 mg/kg 300 mg × 14 days Healthy subjects (11) ND


Table name:
Interacting Drug Interaction
Theophylline Serious and fatal reactions. Avoid concomitant use. Monitor serum level ( 7)
Warfarin Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding ( 7)
Antidiabetic agents Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose ( 7)
Phenytoin Monitor phenytoin level ( 7)
Methotrexate Monitor for methotrexate toxicity ( 7)
Cyclosporine May increase serum creatinine. Monitor serum creatinine ( 7)
Multivalent cation-containing products including antacids, metal cations or didanosine Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin ( 7)


Table name:
Table 3Drugs that Can Increase the Risk of Bleeding
Drug  Class
Specific  Drugs
Anticoagulants 
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin 
Antiplatelet Agents 
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine 
Nonsteroidal Anti-Inflammatory Agents 
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac 
Serotonin Reuptake Inhibitors 
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone 


Table name:
Drug Type of Interaction Effect**

Adenosine

Theophylline blocks adenosine receptors.

Higher doses of adenosine may be required to achieve desired effect.

Alcohol 

A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours.

30% increase 

Allopurinol 

Decreases theophylline clearance at allopurinol doses ≥600 mg/day.

25% increase 

Aminoglutethimide

Increases theophylline clearance by induction of microsomal enzyme activity.

25% decrease 

Carbamazepine

Similar to aminoglutethimide.

30% decrease

Cimetidine

Decreases theophylline clearance by inhibiting cytochrome P450 1A2.

70% increase

Ciprofloxacin

Similar to cimetidine.

40% increase

Clarithromycin

Similar to erythromycin.

25% increase

Diazepam  

Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. 

Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.

Disulfiram 

Decreases theophylline clearance by inhibiting hydroxylation and demethylation.

50% increase 

Enoxacin

Similar to cimetidine.

300% increase

Ephedrine

Synergistic CNS effects.

Increased frequency of nausea, nervousness, and insomnia.

Erythromycin 

 

Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3.

35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.

Estrogen 

Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown.

30% increase 

 

 

Flurazepam

Similar to diazepam.

Similar to diazepam.

Fluvoxamine

Similar to cimetidine.

Similar to cimetidine.

Halothane  

Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines.

Increased risk of ventricular arrhythmias. 

Interferon, human recombinant alpha-A

Decreases theophylline clearance.

100% increase 

Isoproterenol (IV)

Increases theophylline clearance.

20% decrease

Ketamine 

Pharmacologic. 

May lower theophylline seizure threshold

Lithium

Theophylline increases renal lithium clearance.

Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.

Lorazepam

Similar to diazepam.

Similar to diazepam.

Methotrexate (MTX)

Decreases theophylline clearance.

 

20% increase after low dose MTX, higher dose MTX may have a greater effect.

Mexiletine

Similar to disulfiram.

80% increase

Midazolam

Similar to diazepam.

Similar to diazepam.

Moricizine

Increases theophylline clearance.

25% decrease

Pancuronium 

Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition.

Larger dose of pancuronium may be required to achieve neuromuscular blockade.

Pentoxifylline

Decreases theophylline clearance.

 30% increase

Phenobarbital (PB) 

Similar to aminoglutethimide. 

25% decrease after two weeks of concurrent PB.

Phenytoin

Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption.

Serum theophylline and phenytoin concentrations decrease about 40%.

Propafenone 

Decreases theophylline clearance and pharmacologic interaction. 

40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.

Propranolol 

Similar to cimetidine and pharmacologic interaction. 

100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.

Rifampin 

Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity.

20-40% decrease 
St. John’sWort (Hypericum Perforatum) Decrease in theophylline plasma concentrations. Higher doses of theophylline may be required to achieve desired effect. Stopping St. John’s Wort may result in theophylline toxicity.

Sulfinpyrazone

Increase theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline.

20% decrease

Tacrine

Similar to cimetidine, also increases renal clearance of theophylline.

90% increase

Thiabendazole

Decreases theophylline clearance.

190% increase

Ticlopidine

Decreases theophylline clearance.

60% increase

Troleandomycin 

Similar to erythromycin. 

33-100% increase depending on troleandomycin dose.

Verapamil

Similar to disulfiram.

20% increase


Table name:
Drugs That Interfere with Hemostasis
Clinical Impact:
·        Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of Celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.
·        Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:
Monitor patients with concomitant use of celecoxib capsules with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact:
Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].
 
In two studies in healthy volunteers, and in patients with osteoarthritis and established heart disease respectively, celecoxib (200-400 mg daily) has demonstrated a lack of interference with the cardioprotective antiplatelet effect of aspirin (100-325 mg).
Intervention:
Concomitant use of celecoxib capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)].
 
Celecoxib capsules are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:
·        NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).
·        In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:
·        During concomitant use of celecoxib capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.
·        During concomitant use of celecoxib capsules and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)].
·        When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:
Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:
During concomitant use of celecoxib capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Digoxin
Clinical Impact:
The concomitant use of Celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:
During concomitant use of celecoxib capsules and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:
NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:
During concomitant use of celecoxib capsules and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:
Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). celecoxib capsules has no effect on methotrexate pharmacokinetics.
Intervention:
During concomitant use of celecoxib capsules and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:
Concomitant use of celecoxib capsules and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:
During concomitant use of celecoxib capsules and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:
Concomitant use of Celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention:
The concomitant use of Celecoxib with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:
Concomitant use of celecoxib capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:
During concomitant use of celecoxib capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
CYP2C9 Inhibitors or inducers
Clinical Impact:
Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Coadministration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of celecoxib.
Intervention
Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers. [see Clinical Pharmacology ( 12.3)].
CYP2D6 substrates
Clinical Impact:
In vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6 (e.g. atomoxetine), and celecoxib may enhance the exposure and toxicity of these drugs.
Intervention
Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2D6 substrates. [see Clinical Pharmacology ( 12.3)].
Corticosteroids
Clinical Impact:
Concomitant use of corticosteroids with celecoxib capsules may increase the risk of GI ulceration or bleeding.
Intervention
Monitor patients with concomitant use of celecoxib capsules with corticosteroids for signs of bleeding [see Warnings and Precautions (5.2)].


Table name:
TABLE 1. Clinically Significant Drug Interactions with DILAUDID INJECTION and/or DILAUDID-HP INJECTION
Benzodiazepines and other Central Nervous System Depressants (CNS)
Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines and other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.3)].
Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome
Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue DILAUDID INJECTION and DILAUDID-HP INJECTION if serotonin syndrome is suspected.
Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.3)].
If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
Intervention: The use of DILAUDID INJECTION or DILAUDID-HP INJECTION is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples: phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact: May reduce the analgesic effect of DILAUDID INJECTION and DILAUDID-HP INJECTION and/or precipitate withdrawal syndrome.
Intervention: Avoid concomitant use.
Examples: butorphanol, nalbuphine, pentazocine, buprenorphine,
Muscle Relaxants
Clinical Impact: Hydromorphone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of DILAUDID INJECTION and DILAUDID-HP INJECTION and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when DILAUDID INJECTION and DILAUDID-HP INJECTION are used concomitantly with anticholinergic drugs.


Table name:
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Grapefruit juice Avoid grapefruit juice


Table name:
Interacting Drug Interaction
Drugs known to prolong QT interval (e.g., Class IA and Class III anti-arrhythmic agents). Quinine Sulfate Capsules prolong QT interval, ECG abnormalities including QT prolongation and Torsades de Pointes. Avoid concomitant use (5.3).
Other antimalarials (e.g., halofantrine, mefloquine). ECG abnormalities including QT prolongation. Avoid concomitant use (5.3, 7.2).
CYP3A4 inducers or inhibitors Alteration in plasma quinine concentration. Monitor for lack of efficacy or increased adverse events of quinine (7.1).
CYP3A4 and CYP2D6 substrates Quinine is an inhibitor of CYP3A4 and CYP2D6. Monitor for lack of efficacy or increased adverse events of the co-administered drug (7.2).
Digoxin Increased digoxin plasma concentration (5.8, 7.1).


Table name:
  Interacting Agent   Examples
  Drugs that may increase phenytoin serum levels
  Antiepileptic drugs   Ethosuximide, felbamate, oxcarbazepine, methsuximide, topiramate
  Azoles   Fluconazole, ketoconazole, itraconazole, miconazole, voriconazole
  Antineoplastic agents   Capecitabine, fluorouracil
  Antidepressants   Fluoxetine, fluvoxamine, sertraline
  Gastric acid reducing agents   H2 antagonists (cimetidine), omeprazole
  Sulfonamides   Sulfamethizole, sulfaphenazole, sulfadiazine, sulfamethoxazole trimethoprim
  Other   Acute alcohol intake, amiodarone, chloramphenicol, chlordiazepoxide, disulfiram, estrogen, fluvastatin, isoniazid, methylphenidate, phenothiazines, salicylates, ticlopidine, tolbutamide, trazodone, warfarin
 Drugs that may decrease phenytoin serum levels
Antineoplastic agents usually in combination Bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate
Antiviral agents Fosamprenavir, nelfinavir, ritonavir
Antiepileptic drugs Carbamazepine, vigabatrin
Other   Chronic alcohol abuse, diazepam, diazoxide, folic acid, reserpine, rifampin, St. John’s wortb, theophylline
  Drugs that may either increase or decrease phenytoin serum levels
Antiepileptic drugs Phenobarbital, valproate sodium, valproic acid


Table name:
Table 2: Drug-Thyroidal Axis Interactions
  Drug or Drug Class   Effect
  Drugs that may reduce TSH secretion–the reduction is not sustained; therefore, hypothyroidism does not occur
  Dopamine / Dopamine Agonists
Glucocorticoids
Octreotide
  Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day).
  Drugs that alter thyroid hormone secretion
  Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
  Aminoglutethimide
Amiodarone
Iodide(including iodine-containing
  Radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
  Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients.  The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
  Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
  Amiodarone
Iodide(including iodine-containing   
  Radiographic contrast agents)
  Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma).  Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
  Drugs that may decrease T4 absorption, which may result in hypothyroidism
  Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
  Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism.  Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents.  Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
  Drugs that may alter T4 and T3 serum transport  - but FT4 concentration remains normal; and, therefore, the patient remains euthyroid
  Drugs that may increase serum TBG concentration   Drugs that may decrease serum TBG concentration
  Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
  Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
  Drugs that may cause protein-binding site displacement
  Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
  Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4, and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
  Drugs that may alter T4 and T3 metabolism
  Drugs that may increase hepatic metabolism, which may result  in hypothyroidism
  Carbamazepine
Hydantoins
Phenobarbital
Rifampin
  Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
  Drugs that may decrease T4 5’-deiodinase activity
  Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
  Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4  levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
  Miscellaneous
  Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
  Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
  Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors
  (SSRIs; e.g., Sertraline)
  Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of  tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
  Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
  Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
  Cardiac Glycosides   Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
  Cytokines
- Interferon-α
- Interleukin-2
  Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
  Growth Hormones
- Somatrem
- Somatropin
  Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
  Ketamine   Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
  Methylxanthine Bronchodilators
- (e.g., Theophylline)
  Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
  Radiographic Agents   Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
  Sympathomimetics   Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
  Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
  These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.


Table name:
Table 8: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s) Recommendation Comments
Tizanidine Contraindicated Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)].
Theophylline Avoid Use (Plasma Exposure Likely to be Increased and Prolonged) Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions (5.6)] .
Drugs Known to Prolong QT Interval Avoid Use Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.10) and Use in Specific Populations (8.5)].
Oral antidiabetic drugs Use with caution Glucose-lowering effect potentiated Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were coadministered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported . Monitor blood glucose when ciprofloxacin is coadministered with oral antidiabetic drugs [see Adverse Reactions (6.1)] .
Phenytoin Use with caution Altered serum levels of phenytoin (increased and decreased) To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after coadministration of ciprofloxacin with phenytoin.
Cyclosporine Use with caution (transient elevations in serum creatinine) Monitor renal function (in particular serum creatinine) when ciprofloxacin is coadministered with cyclosporine.
Anti-coagulant drugs Use with caution (Increase in anticoagulant effect) The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after coadministration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole Use with caution Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after coadministration with ciprofloxacin [see Warnings and Precautions (5.15)].
Clozapine Use with caution Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after coadministration with ciprofloxacin are advised.
NSAIDs Use with caution Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil Use with caution 2-fold increase in exposure Monitor for sildenafil toxicity [see Pharmacokinetics (12.3)] .
Duloxetine Avoid Use 5-fold increase in duloxetine exposure If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx ®‡ (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products) Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2)]. Decrease ciprofloxacin absorption, resulting in lower serum and urine levels.
Probenecid Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels) Potentiation of ciprofloxacin toxicity may occur.


Table name:
Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme
Inhibitors
Inducers
CYP2C9 
amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast
aprepitant, bosentan, carbamazepine, phenobarbital, rifampin 
CYP1A2 
acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton
montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking 
CYP3A4 
alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton
armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide 


Table name:
Table 18. Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy Risperidone) in Healthy Subjects or Patients with Schizophrenia
 Coadministered Drug  Dosing Schedule  Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio*)  Risperidone Dose recommendation
 Coadministered Drug  Risperidone  AUC  Cmax  
 Enzyme (CYP2D6) Inhibitors          
 Fluoxetine  20 mg/day  2 or 3 mg twice daily  1.4  1.5  Re-evaluate dosing. Do not exceed 8 mg/day
 Paroxetine  10 mg/day  4 mg/day  1.3  -  Re-evaluate dosing. Do not exceed 8 mg/day
   20 mg/day  4 mg/day  1.6  -
   40 mg/day  4 mg/day  1.8  -
 Enzyme (CYP3A/ PgP inducers) Inducers          
 Carbazepine  573 ± 168 mg/day  3 mg twice daily  0.51  0.55  Titrate dose upwards. Do not exceed twice the patient’s usual dose.
 Enzyme (CYP3A) Inhibitors          
 Ranitidine  150 mg twice daily  1 mg single dose  1.2  1.4  Dose adjustment not needed
 Cimetidine  400 mg twice daily  1 mg single dose  1.1  1.3  Dose adjustment not needed
 Erythromycin  500 mg twice daily  1 mg single dose  1.1  0.94  Dose adjustment not needed
           
 Other Drugs          
 Amitriptyline  50 mg twice daily  3 mg twice daily  1.2  1.1  Dose adjustment not needed


Table name:
Table 3: Summary of AED interactions with Topiramate
AED
Co-administered
AED
Concentration
Topiramate
Concentration
a = Plasma concentration increased 25% in some patients, generally those on a b.i.d. dosing regimen of phenytoin.
b = Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration.
AED = Antiepileptic drug.
NE = Not Evaluated.
TPM – Topiramate
Phenytoin NC or 25% increasea 48% decrease
Carbamazepine (CBZ) NC 40% decrease
CBZ epoxideb NC NE
Valproic acid 11% decrease 14% decrease
Phenobarbital NC NE
Primidone NC NE
Lamotrigine NC at TPM doses up to 400 mg/day 15% increase


Table name:
Interacting Drug Interaction
Theophylline Serious and fatal reactions. Avoid concomitant use. Monitor serum level ( 7)
Warfarin Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding ( 7)
Antidiabetic agents Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose ( 7)
Phenytoin Monitor phenytoin level ( 7)
Methotrexate Monitor for methotrexate toxicity ( 7)
Cyclosporine May increase serum creatinine. Monitor serum creatinine ( 7)
Multivalent cation-containing products including antacids, metal cations or didanosine Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin ( 7)


Table name:
Table 2:   Examples of CYP450 Interactions with Warfarin
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide

Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide






Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T and T levels and increase TSH, although all values remain within normal limits in most patients. 4 3
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate










Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
  Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration   Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen





Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid


Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)





Administration of these agents with levothyroxine results in an initial transient increase in FT . Continued administration results in a decrease in serum T and normal FT and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T and T to TBG and transthyretin. An initial increase in serum FT , is followed by return of FT to normal levels with sustained therapeutic serum salicylate concentrations, although total-T levels may decrease by as much as 30%. 4 4 4 4 3 4 4 4
  Drugs that may alter T 4 and T 3 metabolism
  Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin


Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. 4
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)




Administration of these enzyme inhibitors decrease the peripheral conversion of T to T , leading to decreased T levels. However, serum T levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T and T levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T concentrations by 30% with minimal change in serum T levels. However, long-term glucocorticoid therapy may result in slightly decreased T and T levels due to decreased TBG production (see above). 4 3 3 4 3 4 3 4 3 4
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives

Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)


Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin




Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2

Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin

Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of I, I, and Tc. 123 131 99m
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics









These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Figure 1: Effect of interacting drugs on the pharmacokinetics of venlafaxine and active metabolite O-desmethylvenlafaxine (ODV).


Table name:
Interacting Drug Interaction
Theophylline Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin Monitor phenytoin level (7)
Methotrexate Monitor for methotrexate toxicity (7)
Cyclosporine May increase serum creatinine. Monitor serum creatinine (7)
Multivalent cation-containing products including antacids, metal cations or didanosine Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin (7)


Table name:
AED Coadministered AED Concentration Topiramate Concentration
Phenytoin
NC or 25% increasePlasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
48% decrease


Carbamazepine (CBZ)
NC
40% decrease
CBZ epoxideIs not administered but is an active metabolite of carbamazepine.
NC
NE
Valproic acid
11% decrease
14% decrease
Phenobarbital
NC
NE
Primidone
NC
NE
Lamotrigine
NC at TPM doses up to 400 mg/day
13% decrease


Table name:
Concomitant Drug  Effect onConcentration ofLamotrigine orConcomitant Drug Clinical Comment 
Estrogen-containing oralcontraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine   
↓ levonorgestrel
Decreased lamotrigine concentrationsapproximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepineand carbamazepine epoxide  ↓ lamotrigine  
? carbamazepine epoxide
Addition of carbamazepine decreases lamotrigine concentration approximately 40%.May increase carbamazepine epoxide levels.
Lopinavir/ritonavir ↓ lamotrigine Decreased lamotrigine concentrationapproximately 50%.
Atazanavir/ritonavir ↓ lamotrigine Decreased lamotrigine AUCapproximately 32%.
     
Phenobarbital/primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine  
? valproate 
Increased lamotrigine concentrations slightly more than 2-fold.There are conflicting study resultsregarding effect of lamotrigine onvalproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change invalproate concentrations in controlled clinical trials in patients with epilepsy.


Table name:
Drug Description
Heparin Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients
Pyrazinamide Inhibits pyrazinamide-induced hyperuricemia
Uricosuric Agents Effect of probenecid, sulfinpyrazone and phenylbutazone inhibited


Table name:
Phenylephrine:
Drug Effect
Phenylephrine with prior administration of monoamine oxidase inhibitors (MAOI). Cardiac pressor response potentiated. May cause acute hypertensive crisis.
Phenylephrine with tricyclic antidepressants. Pressor response increased.
Phenylephrine with ergot alkaloids. Excessive rise in blood pressure.
Phenylephrine with bronchodilator sympathomimetic agents and with epinephrine or other sympathomimetics. Tachycardia or other arrhythmias may occur.
Phenylephrine with prior administration of propranolol or other β-adrenergic blockers. Cardiostimulating effects blocked.
Phenylephrine with atropine sulfate. Reflex bradycardia blocked; pressor response enhanced.
Phenylephrine with prior administration of phentolamine or other α-adrenergic blockers. Pressor response decreased.
Phenylephrine with diet preparations, such as amphetamines or phenylpropanolamine. Synergistic adrenergic response.


Table name:
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol,can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.The depressant effects of morphine are potentiated by the presence of other CNS depressants. Use of neuroleptics in conjunction with neuraxial morphine may increase the risk of respiratory depression.
Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.5) ].
Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, physotropic drugs, antihistamines, neuroleptics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue DURAMORPH if serotonin syndrome is suspected.
Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.9)].
Intervention: Do not use DURAMORPH in patients taking MAOIs or within 14 days of stopping such treatment. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses of other opioids (such as oxycodone, hydrocodone, oxymorphone, hydrocodone, or buprenorphine) to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
Examples: phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact: May reduce the analgesic effect of DURAMORPH and/or precipitate withdrawal symptoms.
Intervention: Avoid concomitant use.
Examples: Butorphanol, nalbuphine, pentazocine, buprenorphine.
Muscle Relaxants
Clinical Impact: Morphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of DURAMORPH and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when DURAMORPH is used concomitantly with anticholinergic drugs.


Table name:
Drugs That Interfere with Hemostasis       
Clinical Impact: Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen sodium and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of  NAPRELAN with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].
Intervention: Concomitant use of NAPRELAN and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)].
NAPRELAN is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-blockers
Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: During concomitant use of NAPRELAN and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of NAPRELAN and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of NAPRELAN with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].  
Digoxin
Clinical Impact: The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of NAPRELAN and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of NAPRELAN and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of NAPRELAN and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of NAPRELAN and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of NAPRELAN and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention: The concomitant use of naproxen sodium with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of NAPRELAN and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of NAPRELAN and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicityNSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact: Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention: Concomitant administration of antacids such as magnesium oxide or aluminum hydroxid, and sucralfate with NAPRELAN is not recommended.
Cholestyramine
Clinical Impact: Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention: Concomitant administration of cholestyramine with NAPRELAN is not recommended.
Probenecid
Clinical Impact: Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention: Patients simultaneously receiving NAPRELAN and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact: Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin. 
Intervention: Patients simultaneously receiving NAPRELAN and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.


Table name:
Figure 1: Effect of interacting drugs on the pharmacokinetics of venlafaxine and active metabolite O-desmethylvenlafaxine (ODV).


Table name:
Concomitant Drug   Effect onConcentration ofLamotrigine orConcomitant Drug Clinical Comment  
Estrogen-containing oralcontraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine   
↓ levonorgestrel
Decreased lamotrigine concentrationsapproximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepineand carbamazepine epoxide   ↓ lamotrigine  
? carbamazepine epoxide
Addition of carbamazepine decreases lamotrigine concentration approximately 40%.May increase carbamazepine epoxide levels.
Lopinavir/ritonavir ↓ lamotrigine Decreased lamotrigine concentrationapproximately 50%.
Atazanavir/ritonavir ↓ lamotrigine Decreased lamotrigine AUCapproximately 32%.
     
Phenobarbital/primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine  
? valproate  
Increased lamotrigine concentrations slightly more than 2-fold.There are conflicting study resultsregarding effect of lamotrigine onvalproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change invalproate concentrations in controlled clinical trials in patients with epilepsy.


Table name:
Effects on steady-state fexofenadine pharmacokinetics after 7 days of co-administration with fexofenadine hydrochloride 120 mg every 12 hours (two times the recommended twice daily dose) in healthy volunteers (n=24)
Concomitant Drug CmaxSS
(Peak plasma concentration)
AUCss(0–12h)
(Extent of systemic exposure)
Erythromycin
(500 mg every 8 hrs)
+82% +109%
Ketoconazole
(400 mg once daily)
+135% +164%


Table name:
Table 3Drugs that Can Increase the Risk of Bleeding
Drug  Class
Specific  Drugs
Anticoagulants 
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin 
Antiplatelet Agents 
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine 
Nonsteroidal Anti-Inflammatory Agents 
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac 
Serotonin Reuptake Inhibitors 
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone 


Table name:
Factors Dosage Adjustments for Aripiprazole
Known CYP2D6 Poor Metabolizers Administer half of usual dose
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors Administer half of usual dose
Strong CYP2D6 and CYP3A4 inhibitors Administer a quarter of usual dose
Strong CYP3A4 inducers Double usual dose over 1 to 2 weeks


Table name: Indomethacin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of indomethacin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.During concomitant use of indomethacin capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of indomethacin capsules and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Table 2 Clinically Significant Drug Interactions with Indomethacin
Drugs That Interfere with Hemostasis
Clinical Impact:
Intervention: Monitor patients with concomitant use of indomethacin capsules with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].
Intervention: Concomitant use of indomethacin capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. Indomethacin capsules are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:
Intervention:
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. It has been reported that the addition of triamterene to a maintenance schedule of indomethacin capsules resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin capsules and triamterene should not be administered together. Both indomethacin capsules and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin capsules and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently.
Intervention: Indomethacin and triamterene should not be administered together. During concomitant use of indomethacin capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects. Be aware that indomethacin and potassium-sparing diuretics may both be associated with increased serum potassium levels [see Warnings and Precautions (5.6)].
Digoxin
Clinical Impact: The concomitant use of indomethacin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of indomethacin capsules and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of indomethacin capsules and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of indomethacin capsules and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of indomethacin capsules and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of indomethacin capsules and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)]. Combined use with diflunisal may be particularly hazardous because diflunisal causes significantly higher plasma levels of indomethacin. [see Clinical Pharmacology (12.3)]. In some patients, combined use of indomethacin and diflunisal has been associated with fatal gastrointestinal hemorrhage.
Intervention: The concomitant use of indomethacin with other NSAIDs or salicylates, especially diflunisal, is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of indomethacin capsules and pemetrexed may increase the risk of pemetrexed‑associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of indomethacin capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Probenecid
Clinical Impact: When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased.
Intervention: During the concomitant use of indomethacin capsules and probenecid, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect. When increases in the dose of indomethacin are made, they should be made carefully and in small increments.


Table name:
Table 3: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 10 and 20 mg in BPH patients on stable alpha-blocker therapy with tamsulosin 0.4 or 0.8 mg daily (Study 2)
Vardenafil 10 mg
Placebo-subtracted
Vardenafil 20 mg
Placebo-subtracted
Standing SBP -4 (-6.8, -0.3) -4 (-6.8, -1.4)
Supine SBP -5 (-8.2, -0.8) -4 (-6.3, -1.8)


Table name:
Drugs That Interfere with Hemostasis
Clinical Impact: • Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of naproxen or naproxen sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: Concomitant use of naproxen or naproxen sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen or naproxen sodium is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE-inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: • During concomitant use of naproxen or naproxen sodium and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of naproxen or naproxen sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen or naproxen sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact: The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of naproxen or naproxen sodium and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen or naproxen sodium and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of naproxen or naproxen sodium and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of naproxen or naproxen sodium and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of naproxen or naproxen sodium and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of naproxen or naproxen sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of naproxen or naproxen sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact: Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention: Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen or naproxen sodium is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed release tablets are not recommended.
Cholestyramine
Clinical Impact: Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention: Concomitant administration of cholestyramine with naproxen or naproxen sodium is not recommended.
Probenecid
Clinical Impact: Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention: Patients simultaneously receiving naproxen or naproxen sodium and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact: Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention: Patients simultaneously receiving naproxen or naproxen sodium and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.


Table name:
Concomitant Drug  Effect onConcentration ofLamotrigine orConcomitant Drug Clinical Comment 
Estrogen-containing oralcontraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine   
↓ levonorgestrel
Decreased lamotrigine concentrationsapproximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepineand carbamazepine epoxide  ↓ lamotrigine  
? carbamazepine epoxide
Addition of carbamazepine decreases lamotrigine concentration approximately 40%.May increase carbamazepine epoxide levels.
Lopinavir/ritonavir ↓ lamotrigine Decreased lamotrigine concentrationapproximately 50%.
Atazanavir/ritonavir ↓ lamotrigine Decreased lamotrigine AUCapproximately 32%.
     
Phenobarbital/primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine  
? valproate 
Increased lamotrigine concentrations slightly more than 2-fold.There are conflicting study resultsregarding effect of lamotrigine onvalproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change invalproate concentrations in controlled clinical trials in patients with epilepsy.


Table name:
Antiretrovirals
        Clinical Impact: The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology (12.3)]. Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see Clinical Pharmacology (12.3)]. There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole.
        Intervention: Rilpivirine-containing products: Concomitant use with omeprazole is contraindicated [see Contraindications (4)].

Atazanavir: Avoid concomitant use with omeprazole. See prescribing information for atazanavir for dosing information.

Nelfinavir: Avoid concomitant use with omeprazole. See prescribing information for nelfinavir.

Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities.

Other antiretrovirals: See prescribing information for specific antiretroviral drugs.
Warfarin
Clinical Impact: Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
Intervention: Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range.
Methotrexate
Clinical Impact: Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions (5.11)].
Intervention: A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate.
CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam)
Clopidogrel
Clinical Impact: Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology (12.3)].

There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel.
Intervention: Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy [see Warnings and Precautions (5.6)].
Citalopram
Clinical Impact: Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology (12.3)].
Intervention: Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.
Cilostazol
Clinical Impact: Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology (12.3)].
Intervention: Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.
Phenytoin
Clinical Impact: Potential for increased exposure of phenytoin.
Intervention: Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin.
Diazepam
Clinical Impact: Increased exposure of diazepam [see Clinical Pharmacology (12.3)].
Intervention: Monitor patients for increased sedation and reduce the dose of diazepam as needed.
Digoxin
Clinical Impact: Potential for increased exposure of digoxin [see Clinical Pharmacology (12.3)].
Intervention: Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)
Clinical Impact: Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
     Intervention: Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF [see Clinical Pharmacology (12.3)].

See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact: Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated.
Amoxicillin also has drug interactions.
Intervention: See Contraindications, Warnings and Precautions in prescribing information for clarithromycin.

See Drug Interactions in prescribing information for amoxicillin.
Tacrolimus
Clinical Impact: Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.
Intervention: Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact: Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions (5.10), Clinical Pharmacology (12.2)].
  Intervention: Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
Interaction with Secretin Stimulation Test
Clinical Impact: Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention: Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology (12.2)].
False Positive Urine Tests for THC
Clinical Impact: There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.
Intervention: An alternative confirmatory method should be considered to verify positive results.
Other
Clinical Impact: There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram).
Intervention: Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole.


Table name:
AED Coadministered AED Concentration Topiramate Concentration
Phenytoin
NC or 25% increase Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
48% decrease


Carbamazepine (CBZ)
NC
40% decrease
CBZ epoxide Is not administered but is an active metabolite of carbamazepine.
NC
NE
Valproic acid
11% decrease
14% decrease
Phenobarbital
NC
NE
Primidone
NC
NE
Lamotrigine
NC at TPM doses up to 400 mg/day
13% decrease


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
↓ = Decreased (induces lamotrigine glucuronidation).
↑ = Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
Concomitant Drug 
Effect on Concentration of 
Lamotrigine or Concomitant Drug 
Clinical Comment 
Estrogen-containing oral 
contraceptive 
preparations containing 30 mcg 
ethinylestradiol and 150 mcg levonorgestrel 
↓ lamotrigine 

↓ levonorgestrel 
Decreased lamotrigine concentrations approximately 50%. 

Decrease in levonorgestrel component by 19%. 
Carbamazepine and carbamazepine epoxide 
↓ lamotrigine 


? carbamazepine epoxide 
Addition of carbamazepine decreases 
lamotrigine concentration approximately 40%. 
May increase carbamazepine epoxide levels. 
Lopinavir/ritonavir 
↓ lamotrigine 
Decreased lamotrigine concentration approximately 50%. 
Atazanavir/ritonavir 
↓ lamotrigine
Decreased lamotrigine AUC approximately 32%. 
Phenobarbital/Primidone 
↓ lamotrigine 
Decreased lamotrigine concentration
 approximately 40%. 
Phenytoin 
↓ lamotrigine 
Decreased lamotrigine concentration 
approximately 40%. 
Rifampin 
↓ lamotrigine 
Decreased lamotrigine AUC 
approximately 40%. 
Valproate 
↑ lamotrigine

 ? valproate 
Increased lamotrigine concentrations 
slightly more than 2-fold. 
There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.


Table name:
Table 9: Drugs That are Affected by and Affecting Ciprofloxacin Tablets
Drugs That are Affected by C iprofloxacin   Tablets
Drug(s) Recommendation Comments
Tizanidine Contraindicated Concomitant administration of tizanidine and ciprofloxacin tablets is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [ see Contraindications ( 4.2 )]
Theophylline Avoid Use (Plasma Exposure Likely to be Increased and Prolonged) Concurrent administration of ciprofloxacin tablets with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [s ee Warnings and Precautions ( 5.9 ) ] .
Drugs Known to Prolong QT Interval Avoid Use Ciprofloxacin tablets may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions ( 5.11 )   and Use in
Specific Populations ( 8.5 )].
Oral antidiabetic drugs Use with caution Glucose-lowering effect potentiated
Hypoglycemia sometimes severe has been reported when ciprofloxacin tablets and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin tablets is co-administered with oral antidiabetic drugs [see Adverse Reactions ( 6.1)].
Phenytoin Use with caution Altered serum levels of phenytoin (increased and decreased) To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin tablets discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin tablets with phenytoin.
Cyclosporine Use with caution (transient elevations in serum creatinine) Monitor renal function (in particular serum creatinine) when ciprofloxacin tablets is co-administered with cyclosporine.
Anti-coagulant drugs Use with caution (Increase in anticoagulant effect) The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin tablets to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin tablets with an oral anti-coagulant (for example, warfarin).
Methotrexate Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin tablets therapy is indicated.
Ropinirole Use with caution Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin tablets [ see Warnings and Precautions ( 5.16 ) ] .
Clozapine Use with caution Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin tablets are advised.
NSAIDs Use with caution Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil Use with caution Two-fold increase in exposure Monitor for sildenafil toxicity [see  clinical  Pharmacology ( 12.3)].
Duloxetine Avoid Use
Five-fold increase in duloxetine exposure
If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life Ciprofloxacin tablets inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin Tablets
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx®
(didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)
Ciprofloxacin tablets should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration  ( 2.4 ) ] .








Decrease ciprofloxacin tablets absorption, resulting in lower serum and urine levels
Probenecid
Use with caution (interferes with renal tubular secretion of ciprofloxacin tablets and increases ciprofloxacin tablets serum levels)
Potentiation of ciprofloxacin tablets toxicity may occur.


Table name:
Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug Dosing Schedule Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio Change relative to reference) Risperidone Dose Recommendation
Coadministered Drug Risperidone AUC Cmax
Enzyme (CYP2D6) Inhibitors
Fluoxetine 20 mg/day 2 or 3 mg twice daily 1.4 1.5 Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine 10 mg/day 4 mg/day 1.3 - Re-evaluate dosing. Do not exceed 8 mg/day
20 mg/day 4 mg/day 1.6 -
40 mg/day 4 mg/day 1.8 -
Enzyme (CYP3A/PgP inducers) Inducers
Carbamazepine 573 ± 168 mg/day 3 mg twice daily 0.51 0.55 Titrate dose upwards. Do not exceed twice the patient's usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine 150 mg twice daily 1 mg single dose 1.2 1.4 Dose adjustment not needed
Cimetidine 400 mg twice daily 1 mg single dose 1.1 1.3 Dose adjustment not needed
Erythromycin 500 mg four times daily 1 mg single dose 1.1 0.94 Dose adjustment not needed
Other Drugs
Amitriptyline 50 mg twice daily 3 mg twice daily 1.2 1.1 Dose adjustment not needed


Table name:
Table 9 Established and Other Potentially Significant Drug Interactions with Ganciclovir
Name of the Concomitant Drug Change in the Concentration of Ganciclovir or Concomitant Drug Clinical Comment
 Zidovudine
↓ Ganciclovir
↑ Zidovudine
Zidovudine and valganciclovir hydrochloride each have the potential to cause neutropenia and anemia
 Probenecid
↑ Ganciclovir
Patients taking probenecid and valganciclovir hydrochloride should be monitored for evidence of ganciclovir toxicity
 Mycophenolate  Mofetil (MMF)
↔ Ganciclovir (in patients with normal renal function)
↔ MMF (in patients with normal renal function)
Patients with renal impairment should be monitored carefully as levels of MMF metabolites and ganciclovir may increase
 Didanosine
↓ Ganciclovir
↑ Didanosine
Patients should be closely monitored for didanosine toxicity


Table name:
NA – Not available/reported
Digoxin concentrations increased greater than 50%
   Digoxin Serum   
Concentration Increase
   Digoxin AUC   
Increase
Recommendations
Amiodarone 70% NA Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring.
Captopril 58% 39%
Clarithromycin NA 70%
Dronedarone NA 150%
Gentamicin 129-212% NA
Erythromycin 100% NA
Itraconazole 80% NA
Lapatinib NA 180%
Nitrendipine 57% 15%
Propafenone NA 60-270%
Quinidine 100% NA
Ranolazine 50% NA
Ritonavir NA 86%
Telaprevir 50% 85%
Tetracycline 100% NA
Verapamil 50-75% NA
Digoxin concentrations increased less than 50%
Atorvastatin 22% 15% Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring.
Carvedilol 16% 14%
Conivaptan 33% 43%
Diltiazem 20% NA
Indomethacin 40% NA
Nefazodone 27% 15%
Nifedipine 45% NA
Propantheline 24% 24%
Quinine NA 33%
Rabeprazole 29% 19%
Saquinavir 27% 49%
Spironolactone      25% NA
Telmisartan 20-49% NA
Ticagrelor 31% 28%
Tolvaptan 30% 20%
Trimethoprim 22-28% NA
Digoxin concentrations increased, but magnitude is unclear
Alprazolam, azithromycin, cyclosporine, diclofenac, diphenoxylate, epoprostenol, esomeprazole, ibuprofen, ketoconazole, lansoprazole, metformin, omeprazole Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin concentrations decreased
Acarbose, activated charcoal, albuterol, antacids, certain cancer chemotherapy or radiation therapy, cholestyramine, colestipol, extenatide, kaolin-pectin, meals high in bran, metoclopramide, miglitol, neomycin, penicillamine, phenytoin, rifampin, St. John’s Wort, sucralfate, sulfasalazine Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20-40% as necessary.


Table name:
DRUG DESCRIPTION OF INTERACTION
Heparin Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients.
Pyrazinamide Inhibits pyrazinamide-induced hyperuricemia.
Uricosuric Agents Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited.


Table name:
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:
The concomitant use of SSRIs including sertraline hydrochloride and MAOIs increases the risk of serotonin syndrome.
Intervention:
Sertraline hydrochloride is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [See Dosage and Administration (2.5), Contraindications (4), Warnings and Precautions (5.2)].
Examples:
selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue
Pimozide
Clinical Impact:
Increased plasma concentrations of pimozide, a drug with a narrow therapeutic index, may increase the risk of QT prolongation and ventricular arrhythmias.
Intervention:
Concomitant use of pimozide and sertraline hydrochloride is contraindicated [See Contraindications (4)].
Other Serotonergic Drugs
Clinical Impact:
The concomitant use of serotonergic drugs with sertraline hydrochloride increases the risk of serotonin syndrome.
Intervention:
Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of sertraline hydrochloride and/or concomitant serotonergic drugs [See Warnings and Precautions (5.2)].
Examples:
other SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort
Drugs that Interfere with Hemostasis (antiplatelet agents and anticoagulants)
Clinical Impact:
The concurrent use of an antiplatelet agent or anticoagulant with sertraline hydrochloride may potentiate the risk of bleeding.
Intervention:
Inform patients of the increased risk of bleeding associated with the concomitant use of sertraline hydrochloride and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio [See Warnings and Precautions (5.3)].
Examples:
aspirin, clopidogrel, heparin, warfarin
Drugs Highly Bound to Plasma Protein
Clinical Impact:
Sertraline hydrochloride is highly bound to plasma protein. The concomitant use of sertraline hydrochloride with another drug that is highly bound to plasma protein may increase free concentrations of sertraline hydrochloride or other tightly-bound drugs in plasma [See Clinical Pharmacology (12.3)].
Intervention:
Monitor for adverse reactions and reduce dosage of sertraline hydrochloride or other protein-bound drugs as warranted.
Examples:
warfarin
Drugs Metabolized by CYP2D6
Clinical Impact:
Sertraline hydrochloride is a CYP2D6 inhibitor [See Clinical Pharmacology (12.3)]. The concomitant use of sertraline hydrochloride with a CYP2D6 substrate may increase the exposure of the CYP2D6 substrate.
Intervention:
Decrease the dosage of a CYP2D6 substrate if needed with concomitant sertraline hydrochloride use. Conversely, an increase in dosage of a CYP2D6 substrate may be needed if sertraline hydrochloride is discontinued.
Examples:
propafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, thoridazine, tolterodine, venlafaxine
Phenytoin
Clinical Impact:
Phenytoin is a narrow therapeutic index drug. sertraline hydrochloride may increase phenytoin concentrations.
Intervention:
Monitor phenytoin levels when initiating or titrating sertraline hydrochloride. Reduce phenytoin dosage if needed.
Examples:
phenytoin, fosphenytoin


Table name:
TABLE 2. Mean (± S.D.) Pharmacokinetic Parameters for Estradiol, Estrone, and Equilin Following Coadministration of Conjugated Estrogens 0.625 mg and PROMETRIUM Capsules 200 mg for 12 Days to Postmenopausal Women
a Total estrogens is the sum of conjugated and unconjugated estrogen.
  Conjugated Estrogens Conjugated Estrogens plus PROMETRIUM Capsules
Drug Cmax
(ng/mL)
Tmax
(hr)
AUC(0-24h)
(ng × h/mL)
Cmax
(ng/mL)
Tmax
(hr)
AUC(0-24h)
(ng × h/mL)
Estradiol 0.037
± 0.048
12.7
± 9.1
0.676
± 0.737
0.030
± 0.032
17.32
± 1.21
0.561
± 0.572
Estrone
Total a
3.68
± 1.55
10.6
± 6.8
61.3
± 26.36
4.93
± 2.07
7.5
± 3.8
85.9
± 41.2
Equilin
Total a
2.27
± 0.95
6.0
± 4.0
28.8
± 13.0
3.22
± 1.13
5.3
± 2.6
38.1
± 20.2


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( , , , ) 2.6 5.1 7 12.3
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C Protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Table 2. Steady-State Plasma Concentrations of Felbamate when Coadministered with Other AEDs
AED Coadministered AED Concentration Felbamate Concentration
Phenytoin
Valproate No significant effect.
Carbamazepine (CBZ)
Not administered but an active metabolite of carbamazepine.CBZ epoxide

 
Phenobarbital


Table name:
Drug Interactions Associated with Increased Risk of  Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice Avoid grapefruit juice


Table name:
Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol, famotidine nizatidine
systemic and inhaled felodipine norfloxacin
amoxicillin finasteride ofloxacin
ampicillin, hydrocortisone omeprazole
with or without isoflurane prednisone, prednisolone
sulbactam isoniazid ranitidine
atenolol isradipine rifabutin
azithromycin influenza vaccine roxithromycin
caffeine, ketoconazole sorbitol
  dietary ingestion lomefloxacin (purgative doses do not
cefaclor mebendazole inhibit theophylline
co-trimoxazole medroxyprogesterone absorption)
(trimethoprim and methylprednisolone sucralfate
sulfamethoxazole) metronidazole terbutaline, systemic
diltiazem metoprolol terfenadine
dirithromycin nadolol tetracycline
enflurane nifedipine tocainide


Table name:
Interacting Drug Interaction
Antacids, sucralfate, multivitamins, and other products containing multivalent cations Moxifloxacin absorption is decreased. Administer AVELOX Tablet at least 4 hours before or 8 hours after these products. (2.2, 7.1, 12.3, 17.2)
Warfarin Anticoagulant effect of warfarin may be enhanced. Monitor prothrombin time/INR, watch for bleeding. (6.4, 7.2, 12.3)
Class IA and Class III antiarrhythmics: Proarrhythmic effect may be enhanced. Avoid concomitant use. (5.3, 7.4)


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
↓= Decreased (induces lamotrigine gluronidation).
↑= Increased (inhibits lamotrigine gluronidation).
?= Conflicting data.
Concomitant Drug
Effect on Concentration of 
Lamotrigine or Concomitant Drug
Clinical Comment
Estrogen-containing oral 
contraceptive preparation containing 
30 mcg ethinylestradiol and 
150 mcg levonorgestrel 
↓ lamotrigine 



↓ levonorgestrel 
Decreased lamotrigine levels approximately 50%. 



Decrease in levonorgestrel component by 19%. 
Carbamazepine (CBZ) and CBZ epoxide 
↓ lamotrigine 



? CBZ epoxide 
Addition of carbamazepine decreases lamotrigine 
concentration approximately 40%. 


May increase CBZ epoxide levels 
Phenobarbital/Primidone 
↓ lamotrigine 
Decreased lamotrigine concentration approximately 40%. 
Phenytoin (PHT) 
↓ lamotrigine 
Decreased lamotrigine concentration approximately 40%. 
Rifampin 
↓ lamotrigine 
Decreased lamotrigine AUC approximately 40%. 
Valproate 
↑ lamotrigine  


? valproate 
Increased lamotrigine concentrations slightly
more than 2-fold. 

Decreased valproate concentrations an average of
25% over a 3-week period then stabilized in healthy
volunteers; no change in controlled clinical trials in
epilepsy patients. 


Table name:
Factors
Dosage  Adjustments  for  Aripiprazole  Tablets
Known CYP2D6 Poor Metabolizers
Administer half of usual dose
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors
Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors
Administer half of usual dose
Strong CYP2D6 and CYP3A4
inhibitors
Administer a quarter of usual dose
Strong CYP3A4 inducers
Double usual dose over 1 to 2 weeks


Table name:
Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) VIAGRA 100 mg
Supine 7.9 (4.6, 11.1)
Standing

4.3 (-1.8,10.3)



Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine
↓ levonorgestrel
Decreased lamotrigine concentrations approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide ↓ lamotrigine
? carbamazepine epoxide
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels.
Lopinavir/ritonavir ↓ lamotrigine Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir ↓ lamotrigine Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine
? valproate
Increased lamotrigine concentrations slightly more than 2 fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant  Drug
Effect  on  Concentration  of  Lamotrigine  or 
Concomitant  Drug
Clinical  Comment 
↓= Decreased (induces lamotrigine gluronidation).
↑= Increased (inhibits lamotrigine glucuronidation).
?= Conflicting data.
Estrogen-containing oral 
contraceptive preparations 
containing 30 mcg ethinylestradiol 
and 150 mcg levonorgestrel
↓ lamotrigine




Decreased lamotrigine levels 
approximately 50%.




↓ levonorgestrel
Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and 
CBZ epoxide
↓ lamotrigine

Addition of carbamazepine decreases lamotrigine 
concentration approximately 40%.


? CBZ epoxide
May increase CBZ epoxide levels
Phenobarbital/Primidone
↓ lamotrigine
Decreased lamotrigine 
concentration approximately 40%.
Phenytoin (PHT)
↓ lamotrigine
Decreased lamotrigine 
concentration approximately 40%
Rifampin
↓ lamotrigine
Decreased lamotrigine AUC 
approximately 40%
Valproate
↑ lamotrigine

Increased lamotrigine concentrations slightly 
more than 2-fold.


? valproate
Decreased valproate concentrations an average of 
25% over a 3-week period then stabilized in healthy volunteers; 
no change in controlled clinical trials in epilepsy patients.



Table name:
Drugs That Interfere with Hemostasis
Clinical Impact: • Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone.
• Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of naproxen delayed-release tablets with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity ).
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: Concomitant use of naproxen delayed-release tablets and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity).
Naproxen delayed-release tablets are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).
• In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: • During concomitant use of naproxen delayed-release tablets and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.
• During concomitant use of naproxen delayed-release tablets and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia).
When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention During concomitant use of naproxen delayed-release tablets with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact: The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of naproxen delayed-release tablets and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen delayed-release tablets and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of naproxen delayed-release tablets and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of naproxen delayed-release tablets and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of naproxen delayed-release tablets and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of naproxen delayed-release tablets and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of naproxen delayed-release tablets and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.

NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.

In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact: Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention: Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen delayed-release tablets is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed-release tablets is not recommended.
Cholestyramine
Clinical Impact: Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention: Concomitant administration of cholestyramine with naproxen delayed-release tablets is not recommended.
Probenecid
Clinical Impact: Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention: Patients simultaneously receiving naproxen delayed-release tablets and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact: Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention: Patients simultaneously receiving naproxen delayed-release tablets and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.


Table name:
Table 6: Predicted Drug Interactions with Didanosine Delayed-Release Capsules
Drug or Drug Class Effect Clinical Comment
↑ Indicates increase.
a Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that cause pancreatic toxicity is required, suspension of didanosine delayed-release capsules is recommended [see Warnings and Precautions (5.1)].
b [See Warnings and Precautions (5.6).]

   Drugs that may cause pancreatic toxicity

↑ risk of pancreatitis

   Use only with extreme caution.a

   Neurotoxic drugs

↑ risk of neuropathy

   Use with caution.b


Table name:
Table 4 Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction
Concomitant Drug Class: Drug Name Effect on Concentration Clinical Comment
Antacids:

  antacids
  (e.g., aluminium, magnesium hydroxide, or calcium carbonate)
↔ rilpivirine
(antacids taken at least 2 hours before or at least 4 hours after rilpivirine)

↓ rilpivirine (concomitant intake)
The combination of COMPLERA and antacids should be used with caution as coadministration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). Antacids should only be administered either at least 2 hours before or at least 4 hours after COMPLERA.
Azole Antifungal Agents:

  fluconazole
  itraconazole
  ketoconazole
  posaconazole
  voriconazole
↑ rilpivirineThe interaction was evaluated in a clinical study. All other drug-drug interactions shown are predicted. , This interaction study has been performed with a dose higher than the recommended dose for rilpivirine. The dosing recommendation is applicable to the recommended dose of rilpivirine 25 mg once daily.
↓ ketoconazole ,
Concomitant use of COMPLERA with azole antifungal agents may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). No dose adjustment is required when COMPLERA is coadministered with azole antifungal agents. Clinically monitor for breakthrough fungal infections when azole antifungals are coadministered with COMPLERA.
H2-Receptor Antagonists:

  cimetidine
  famotidine
  nizatidine
  ranitidine
↔ rilpivirine ,
(famotidine taken 12 hours before rilpivirine or 4 hours after rilpivirine)

↓ rilpivirine ,
(famotidine taken 2 hours before rilpivirine)
The combination of COMPLERA and H2-receptor antagonists should be used with caution as coadministration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). H2-receptor antagonists should only be administered at least 12 hours before or at least 4 hours after COMPLERA.
Macrolide or Ketolide Antibiotics:

  clarithromycin
  erythromycin
  telithromycin
↑ rilpivirine
↔ clarithromycin
↔ erythromycin
↔ telithromycin
Concomitant use of COMPLERA with clarithromycin, erythromycin or telithromycin may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). Where possible, alternatives such as azithromycin should be considered.
Narcotic Analgesics:

  methadone
↓ R(–) methadone
↓ S(+) methadone
↔ rilpivirine
↔ methadone (when used with tenofovir)
No dose adjustments are required when initiating coadministration of methadone with COMPLERA. However, clinical monitoring is recommended as methadone maintenance therapy may need to be adjusted in some patients.


Table name:

albuterol, systemic and inhaled

mebendazole

amoxicillin

medroxyprogesterone

ampicillin, with or without

methylprednisolone

sulbactam

metronidazole

atenolol

metoprolol

azithromycin

nadolol

caffeine, dietary ingestion

nifedipine

cefaclor

nizatidine

co-trimoxazole (trimethoprim and

sulfamethoxazole)

norfloxacin

ofloxacin

diltiazem

omeprazole

dirithromycin

prednisone, prednisolone

enflurane

ranitidine

famotidine

rifabutin

felodipine

roxithromycin

finasteride

Sorbitol (purgative doses do not inhibit

hydrocortisone

theophylline absorption)

isoflurane

sucralfate

isoniazid

terbutaline, systemic

isradipine

terfenadine

influenza vaccine

tetracycline

ketoconazole

tocainide

lomefloxacin

 


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
↓= Decreased (induces lamotrigine glucuronidation).
↑= Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine Decreased lamotrigine concentrations approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? carbamazepine epoxide May increase carbamazepine epoxide levels.
Lopinavir/ritonavir ↓ lamotrigine Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir ↓ lamotrigine Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine Increased lamotrigine concentrations slightly more than 2-fold.
? valproate There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.


Table name:
Table 3 Clinically Relevant Interactions Affecting Drugs Co-Administered with Omeprazole and Interaction with Diagnostics
Antiretrovirals

Clinical  Impact :
The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. 



o  Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology (12.3)].

o  Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see clinical Pharmacology (12.3)].

o   There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole. 
Intervention
Rilpivirine-containing products: Concomitant use with omeprazole delayed-release capsule is contraindicated [see Contraindications (4)].

Atazanavir: Avoid concomitant use with omeprazole delayed-release capsules. See prescribing information for atazanavir for dosing information. 

Nelfinavir: Avoid concomitant use with omeprazole delayed-release capsules. See prescribing information for nelfinavir. 

Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities. 

Other antiretrovirals: See prescribing information for specific antiretroviral drugs.
Warfarin 

Clinical  Impact
Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. 
Intervention
Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range. 
Methotrexate 

Clinical  Impact
Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions (5.11)].
Intervention
A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate. 
CYP2C19  Substrates  ( e . g .,  clopidogrel citalopram cilostazol phenytoin diazepam

Clopidogrel

Clinical  Impact
Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology (12.3)]. There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel.
Intervention
Avoid concomitant use with omeprazole delayed-release capsules. Consider use of alternative anti-platelet therapy [see Warnings and Precautions (5.6)].
Citalopram 

Clinical  Impact
Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology (12.3)].
Intervention
Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram. 
Cilostazol 

Clinical  Impact
Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology (12.3)].
Intervention
Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol. 
Phenytoin 

Clinical  Impact
Potential for increased exposure of phenytoin. 
Intervention
Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin. 
Diazepam 

Clinical  Impact
Increased exposure of diazepam [see Clinical Pharmacology (12.3)].
Intervention
Monitor patients for increased sedation and reduce the dose of diazepam as needed. 
Digoxin 

Clinical  Impact
Potential for increased exposure of digoxin [see Clinical Pharmacology (12.3)].
Intervention
Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information. 
Drugs  Dependent  on  Gastric  pH  for  Absorption  ( e . g .,  iron  salts erlotinib dasatinib nilotinib mycophenolate  mofetil ketoconazole / itraconazole

Clinical  Impact
Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
Intervention
Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole delayed-release capsules and MMF. Use omeprazole delayed-release capsules with caution in transplant patients receiving MMF [see Clinical Pharmacology (12.3)]. See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination  Therapy  with  Clarithromycin  and  Amoxicillin 

Clinical  Impact
Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions. 
Intervention
See Contraindications Warnings and Precautions in prescribing information for clarithromycin. 
See Drug  Interactions in prescribing information for amoxicillin.
Tacrolimus 

Clinical  Impact
Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19
Intervention
Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus. 
Interactions  with  Investigations  of  Neuroendocrine  Tumors 

Clinical  Impact
Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions (5.10), Clinical Pharmacology (12.2)].
Intervention
Temporarily stop omeprazole delayed-release capsules treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary. 
Interaction  with  Secretin  Stimulation  Test 

Clinical  Impact
Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma. 
Intervention
Temporarily stop omeprazole delayed-release capsules treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology (12.2)].
False  Positive  Urine  Tests  for  THC 

Clinical  Impact
There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs. 
Intervention
An alternative confirmatory method should be considered to verify positive results.
Other 

Clinical  Impact
There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram). 
Intervention
Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole delayed-release capsules. 


Table name:
Interacting Drug Interaction
Drugs known to prolong QT interval (e.g., Class IA and Class III antiarrhythmic agents). QUALAQUIN prolongs QT interval, ECG abnormalities including QT prolongation and Torsades des Pointes. Avoid concomitant use (5.3).
Other antimalarials (e.g., halofantrine, mefloquine). ECG abnormalities including QT prolongation. Avoid concomitant use (5.3, 7.2).
CYP3A4 inducers or inhibitors Alteration in plasma quinine concentration. Monitor for lack of efficacy or increased adverse events of quinine (7.1).
CYP3A4 and CYP2D6 substrates Quinine is an inhibitor of CYP3A4 and CYP2D6. Monitor for lack of efficacy or increased adverse events of the co-administered drug (7.1).
Digoxin Increased digoxin plasma concentration (5.8, 7.1).


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Figure 2: Effect of venlafaxine on the pharmacokinetics interacting drugs and their active metabolites.


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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor
(boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s)
Recommendation
Comments
Tizanidine
Contraindicated
Concomitant administration of tizanidine and ciprofloxacin  is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2) ].
Theophylline
Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)
Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate. [See Warnings and Precautions (5.9) .]
Drugs Known to Prolong QT Interval
Avoid Use
 
Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see  Warnings and Precautions (5.11) and Use in   Specific Populations (8.5) ].
Oral antidiabetic drugs
Use with caution Glucose-lowering effect potentiated
Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs. [See Adverse Reactions (6.1) .]
Phenytoin
Use with caution Altered serum levels of phenytoin
(increased and decreased)
 
To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin with phenytoin.
Cyclosporine
Use with caution (transient elevations in serum creatinine)
Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs
Use with caution (Increase in anticoagulant effect)
The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate
Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels
Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole
Use with caution
Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin [see Warnings and Precautions (5.16) ].
Clozapine
Use with caution
Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs
Use with caution
Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies in and postmarketing.
Sildenafil
Use with caution Two-fold increase in exposure
Monitor for sildenafil toxicity (see Clinical Pharmacology (12.3 )].
Duloxetine
Avoid Use
Five-fold increase in duloxetine exposure
If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives
Use with caution Reduced clearance resulting in elevated levels and prolongation
of serum half-life
Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx® (didanosine) chewable/ buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)
Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2.4)] .
Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid
Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)
Potentiation of ciprofloxacin toxicity may occur.


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Table 1: Clinically Significant Drug Interactions with DILAUDID
Benzodiazepines and other Central Nervous System (CNS) Depressants
Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.5)].
Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome
Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue DILAUDID Oral Solution or DILAUDID Tablets if serotonin syndrome is suspected.
Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.3)].
If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
Intervention: The use of DILAUDID Oral Solution or DILAUDID Tablets is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples: phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact: May reduce the analgesic effect of DILAUDID Oral Solution or DILAUDID Tablets and/or precipitate withdrawal symptoms.
Intervention: Avoid concomitant use.
Examples: butorphanol, nalbuphine, pentazocine, buprenorphine,
Muscle Relaxants
Clinical Impact: Hydromorphone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of DILAUDID Oral Solution or DILAUDID Tablets and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when DILAUDID Oral Solution or DILAUDID Tablets is used concomitantly with anticholinergic drugs.


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Table 3: Drugs that Can Increase the Risk of Bleeding
 Drug Class  Specific Drugs
 Anticoagulants  argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
 Antiplatelet Agents  aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
 Nonsteroidal Anti-Inflammatory Agents  celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
 Serotonin Reuptake Inhibitors  citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


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Table 5: Effect of Other Drugs on VYVANSE
Concomitant Drug Name or Drug Class Clinical Rationale Clinical Recommendation
Acidifying and Alkalinizing Agents Ascorbic acid and other agents that acidify urine increase urinary excretion and decrease the half-life of amphetamine. Sodium bicarbonate and other agents that alkalinize urine decrease urinary excretion and extend the half-life of amphetamine. Adjust the dose accordingly [see Dosage and Administration (2.6)]


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Table 3Drugs that Can Increase the Risk of Bleeding
Drug  Class
Specific  Drugs
Anticoagulants 
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin 
Antiplatelet Agents 
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine 
Nonsteroidal Anti-Inflammatory Agents 
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac 
Serotonin Reuptake Inhibitors 
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone 


Table name:
Table II. Clinically significant drug interactions with theophylline*.
DrugType of InteractionEffect**
AdenosineTheophylline blocks adenosine receptors.Higher doses of adenosine may be required to achieve desired effect.
AlcoholA single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours.30% increase
AllopurinolDecreases theophylline clearance at allopurinol doses ≥600 mg/day.25% increase
AminoglutethimideIncreases theophylline clearance by induction of microsomal enzyme activity.25% decrease
Carbamazepine Similar to aminoglutethimide. 30% decrease
CimetidineDecreases theophylline clearance by inhibiting cytochrome P450 1A2.70% increase
Ciprofloxacin Similar to cimetidine. 40% increase
Clarithromycin Similar to erythromycin. 25% increase
DiazepamBenzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors.Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
DisulfiramDecreases theophylline clearance by inhibiting hydroxylation and demethylation.50% increase
EnoxacinSimilar to cimetidine. 300% increase
EphedrineSynergistic CNS effectsIncreased frequency of nausea, nervousness, and insomnia.
ErythromycinErythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3.35% increase. Erythromycin steady-stateserum concentrations decrease by a similar amount.
EstrogenEstrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown.30% increase
Flurazepam Similar to diazepam. Similar to diazepam.
Fluvoxamine Similar to cimetidine. Similar to cimetidine.
HalothaneHalothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines.Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-ADecreases theophylline clearance. 100% increase
Isoproterenol (IV)Increases theophylline clearance.20% decrease
KetaminePharmacologicMay lower theophylline seizure threshold.
LithiumTheophylline increases renal lithium clearance.Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam Similar to diazepam. Similar to diazepam.
Methotrexate (MTX) Decreases theophylline clearance.20% increase after low dose MTX, higher dose MTX may have a greater effect.
Mexiletine Similar to disulfiram. 80% increase
Midazolam Similar to diazepam. Similar to diazepam.
Moricizine Increases theophylline clearance. 25% decrease
PancuroniumTheophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition.Larger dose of pancuronium may be required to achieve neuromuscular blockade.
Pentoxifylline Decreases theophylline clearance.30% increase
Phenobarbital (PB)Similar to aminoglutethimide.25% decrease after two weeks of concurrent PB.
PhenytoinPhenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption.Serum theophylline and phenytoin concentrations decrease about 40%.
PropafenoneDecreases theophylline clearance and pharmacologic interaction.40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
PropranololSimilar to cimetidine and pharmacologic interaction.100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
RifampinIncreases theophylline clearance by increasing cytochrome P4501A2 and 3A3 activity.20-40% decrease
SulfinpyrazoneIncreases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline.20% decrease
TacrineSimilar to cimetidine, also increases renal clearance of theophylline.90% increase
Thiabendazole Decreases theophylline clearance.190% increase
Ticlopidine Decreases theophylline clearance.60% increase
Troleandomycin Similar to erythromycin. 33-100% increase depending on troleandomycin dose.
Verapamil Similar to disulfiram. 20% increase
* Refer to PRECAUTIONS, Drug Interactions for further information regarding table.
** Average effect on steady state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.


Table name:
Interacting Drug Interaction
Theophylline Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin Monitor phenytoin level (7)
Methotrexate Monitor for methotrexate toxicity (7)
Cyclosporine May increase serum creatinine. Monitor serum creatinine (7)
Multivalent cation-containing products including antacids, metal cations or didanosine Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin (7)


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Table 7: Summary of AED Interactions with Oxcarbazepine
AED Coadministered Dose of AED (mg/day) Oxcarbazepine dose (mg/day) Influence of Oxcarbazepine on AED Concentration (Mean change, 90% Confidence Interval) Influence of AED on MHD Concentration (Mean change, 90% Confidence Interval)
Carbamazepine 400 to 2000 900 nc1 40% decrease [Cl: 17% decrease, 57% decrease]
Phenobarbital 100 to 150 600 to 1800 14% increase [Cl: 2% increase, 24% increase] 25% decrease [Cl: 12% decrease, 51% decrease]
Phenytoin 250 to 500 600 to 1800 >1200 to 2400 nc1,2 up to 40% increase3 [Cl: 12% increase, 60% increase] 30% decrease [Cl: 3% decrease, 48% decrease]
Valproic acid 400 to 2800 600 to 1800 nc1 18% decrease [Cl: 13% decrease, 40% decrease]
1nc denotes a mean change of less than 10% 2Pediatrics 3Mean increase in adults at high oxcarbazepine doses


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
↓ = Decreased (induces lamotrigine glucuronidation).
↑ = Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
Concomitant Drug 
Effect on Concentration of 
Lamotrigine or Concomitant Drug 
Clinical Comment 
Estrogen-containing oral 
contraceptive 
preparations containing 30 mcg 
ethinylestradiol and 150 mcg levonorgestrel 
↓ lamotrigine 

↓ levonorgestrel 
Decreased lamotrigine concentrations approximately 50%. 

Decrease in levonorgestrel component by 19%. 
Carbamazepine and carbamazepine epoxide 
↓ lamotrigine 


? carbamazepine epoxide 
Addition of carbamazepine decreases 
lamotrigine concentration approximately 40%. 
May increase carbamazepine epoxide levels. 
Lopinavir/ritonavir 
↓ lamotrigine 
Decreased lamotrigine concentration approximately 50%. 
Atazanavir/ritonavir 
↓ lamotrigine
Decreased lamotrigine AUC approximately 32%. 
Phenobarbital/Primidone 
↓ lamotrigine 
Decreased lamotrigine concentration
 approximately 40%. 
Phenytoin 
↓ lamotrigine 
Decreased lamotrigine concentration 
approximately 40%. 
Rifampin 
↓ lamotrigine 
Decreased lamotrigine AUC 
approximately 40%. 
Valproate 
↑ lamotrigine

 ? valproate 
Increased lamotrigine concentrations 
slightly more than 2-fold. 
There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.


Table name:
Drugs That Interfere with Hemostasis
Clinical Impact: • Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of naproxen or naproxen sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: Concomitant use of naproxen or naproxen sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen or naproxen sodium is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE-inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: • During concomitant use of naproxen or naproxen sodium and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of naproxen or naproxen sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen or naproxen sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact: The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of naproxen or naproxen sodium and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen or naproxen sodium and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of naproxen or naproxen sodium and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of naproxen or naproxen sodium and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of naproxen or naproxen sodium and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of naproxen or naproxen sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of naproxen or naproxen sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact: Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention: Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen or naproxen sodium is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed release tablets are not recommended.
Cholestyramine
Clinical Impact: Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention: Concomitant administration of cholestyramine with naproxen or naproxen sodium is not recommended.
Probenecid
Clinical Impact: Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention: Patients simultaneously receiving naproxen or naproxen sodium and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact: Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention: Patients simultaneously receiving naproxen or naproxen sodium and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.


Table name:
Interacting Drug Interaction
Theophylline Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin Monitor phenytoin level (7)
Methotrexate Monitor for methotrexate toxicity (7)
Cyclosporine May increase serum creatinine. Monitor serum creatinine (7)
Multivalent cation-containing products including antacids, metal cations or didanosine Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin (7)


Table name:
Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.*
*    Refer to PRECAUTIONS, Drug Interactions for information regarding table.
 albuterol, systemic and inhaled  hydrocortisone  ofloxacin
 amoxicillin  isoflurane  omeprazole
 ampicillin, with or without  isoniazid  prednisone, prednisolone
   sulbactam  isradipine  ranitidine
 atenolol  influenza vaccine  rifabutin
 azithromycin  ketoconazole  roxithromycin
 caffeine, dietary ingestion  lomefloxacin  sorbitol
 cefaclor  mebendazole    (purgative doses do
 co-trimoxazole (trimethoprim  medroxyprogesterone    not inhibit theophylline
    and sulfamethoxazole)  methylprednisolone    absorption)
 diltiazem  metronidazole  sucralfate
 dirithromycin  metoprolol  terbutaline,systemic
 enflurane  nadolol  terfenadine
 famotidine  nifedipine  tetracycline
 felodipine  nizatidine  tocainide
 finasteride  norfloxacin


Table name: Use of sildenafil (REVATIO) is contraindicated when used for the treatment of PAH [see Contraindications (4)]. The following dose adjustments are recommended for use of tadalafil (ADCIRCA®) with LEXIVA: Coadministration of ADCIRCA in patients on LEXIVA: In patients receiving LEXIVA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Coadministration of LEXIVA in patients on ADCIRCA: Avoid use of ADCIRCA during the initiation of LEXIVA. Stop ADCIRCA at least 24 hours prior to starting LEXIVA. After at least one week following the initiation of LEXIVA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: LEXIVA: Sildenafil: 25 mg every 48 hours. Tadalafil: no more than 10 mg every 72 hours. Vardenafil: no more than 2.5 mg every 24 hours. LEXIVA/ritonavir: Sildenafil: 25 mg every 48 hours.Tadalafil: no more than 10 mg every 72 hours.Vardenafil: no more than 2.5 mg every 72 hours.Use with increased monitoring for adverse events.
Table 7. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class: Drug Name Effect on Concentration of Amprenavir or Concomitant Drug Clinical Comment
HCV/HIV-Antiviral Agents
HCV protease inhibitor: Boceprevir LEXIVA: ↓Amprenavir (predicted) ↔ or ↓Boceprevir (predicted) LEXIVA/ritonavir: ↓Amprenavir (predicted) ↓Boceprevir (predicted) Coadministration of LEXIVA or LEXIVA/ritonavir and boceprevir is not recommended.
HCV protease inhibitor: Simeprevir LEXIVA: ↔Amprenavir (predicted) ↑ or ↓Simeprevir (predicted) LEXIVA/ritonavir: ↔Amprenavir (predicted) ↑Simeprevir (predicted) Coadministration of LEXIVA or LEXIVA/ritonavir and simeprevir is not recommended.
HCV protease inhibitor: Paritaprevir (coformulated with ritonavir and ombitasvir and coadministered with dasabuvir) LEXIVA: ↑Amprenavir (predicted) ↑ or ↔Paritaprevir (predicted) LEXIVA/ritonavir: ↑ or ↔Amprenavir (predicted) ↑Paritaprevir (predicted) Appropriate doses of the combinations with respect to safety and efficacy have not been established. LEXIVA 1400 mg once daily may be considered when coadministered with paritaprevir/ritonavir/ombitasvir/ dasabuvir. Coadministration of LEXIVA/ritonavir and paritaprevir/ritonavir/ombitasvir/ dasabuvir is not recommended.
Non-nucleoside reverse transcriptase inhibitor: Efavirenza LEXIVA: ↓Amprenavir LEXIVA/ritonavir: ↓Amprenavir Appropriate doses of the combinations with respect to safety and efficacy have not been established. An additional 100 mg/day (300 mg total) of ritonavir is recommended when efavirenz is administered with LEXIVA/ritonavir once daily. No change in the ritonavir dose is required when efavirenz is administered with LEXIVA plus ritonavir twice daily.
Non-nucleoside reverse transcriptase inhibitor: Nevirapinea LEXIVA: ↓Amprenavir ↑Nevirapine LEXIVA/ritonavir: ↓Amprenavir ↑Nevirapine Coadministration of nevirapine and LEXIVA without ritonavir is not recommended. No dosage adjustment required when nevirapine is administered with LEXIVA/ritonavir twice daily. The combination of nevirapine administered with LEXIVA/ritonavir once-daily regimen has not been studied.
HIV protease inhibitor: Atazanavira LEXIVA: Interaction has not been evaluated. LEXIVA/ritonavir: ↓Atazanavir ↔Amprenavir Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV protease inhibitors: Indinavira, nelfinavira LEXIVA: ↑Amprenavir Effect on indinavir and nelfinavir is not well established. LEXIVA/ritonavir: Interaction has not been evaluated. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV protease inhibitors: Lopinavir/ritonavira ↓Amprenavir ↓Lopinavir An increased rate of adverse events has been observed. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV protease inhibitor: Saquinavira LEXIVA: ↓Amprenavir Effect on saquinavir is not well established. LEXIVA/ritonavir: Interaction has not been evaluated. Appropriate doses of the combination with respect to safety and efficacy have not been established.
HIV integrase inhibitor: Raltegravira LEXIVA: ↓Amprenavir ↓Raltegravir LEXIVA/ritonavir: ↓Amprenavir ↓Raltegravir Appropriate doses of the combination with respect to safety and efficacy have not been established.
HIV integrase inhibitor: Dolutegravira LEXIVA/ritonavir: ↓Dolutegravir The recommended dose of dolutegravir is 50 mg twice daily when coadministered with LEXIVA/ritonavir. Use an alternative combination where possible in patients with known or suspected integrase inhibitor resistance.
HIV CCR5 co-receptor antagonist: Maraviroca LEXIVA/ritonavir: ↓Amprenavir ↑Maraviroc No dosage adjustment required for LEXIVA/ritonavir. The recommended dose of maraviroc is 150 mg twice daily when coadministered with LEXIVA/ritonavir. LEXIVA should be given with ritonavir when coadministered with maraviroc.
Other Agents
Antiarrhythmics: Amiodarone, lidocaine (systemic), and quinidine ↑Antiarrhythmics Use with caution. Increased exposure may be associated with life-threatening reactions such as cardiac arrhythmias. Therapeutic concentration monitoring, if available, is recommended for antiarrhythmics.
Anticoagulant: Warfarin Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants: Carbamazepine, phenobarbital, phenytoin Phenytoina LEXIVA: ↓Amprenavir LEXIVA/ritonavir: ↑Amprenavir ↓Phenytoin Use with caution. LEXIVA may be less effective due to decreased amprenavir plasma concentrations in patients taking these agents concomitantly. Plasma phenytoin concentrations should be monitored and phenytoin dose should be increased as appropriate. No change in LEXIVA/ritonavir dose is recommended.
Antidepressant: Paroxetine, trazodone ↓Paroxetine ↑Trazodone Any paroxetine dose adjustment should be guided by clinical effect (tolerability and efficacy). Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as LEXIVA, the combination should be used with caution and a lower dose of trazodone should be considered.
Antifungals: Ketoconazolea, itraconazole ↑Ketoconazole ↑Itraconazole Increase monitoring for adverse events. LEXIVA: Dose reduction of ketoconazole or itraconazole may be needed for patients receiving more than 400 mg ketoconazole or itraconazole per day. LEXIVA/ritonavir: High doses of ketoconazole or itraconazole (greater than 200 mg/day) are not recommended.
Anti-gout: Colchicine ↑Colchicine Patients with renal or hepatic impairment should not be given colchicine with LEXIVA/ritonavir. LEXIVA/ritonavir and coadministration of colchicine: Treatment of gout flares: 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.
If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.
Treatment of familial Mediterranean fever (FMF): Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). LEXIVA and coadministration of colchicine: Treatment of gout flares: 1.2 mg (2 tablets) x 1 dose. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg twice a day or 0.6 mg once a day.
If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once a day.
Treatment of FMF: Maximum daily dose of 1.2 mg (may be given as 0.6 mg twice a day).
Antimycobacterial: Rifabutina ↑Rifabutin and rifabutin metabolite A complete blood count should be performed weekly and as clinically indicated to monitor for neutropenia. LEXIVA: A dosage reduction of rifabutin by at least half the recommended dose is required. LEXIVA/ritonavir: Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (a maximum dose of 150 mg every other day or 3 times per week).
Antipsychotics: Quetiapine LEXIVA/ritonavir: ↑Quetiapine Initiation of LEXIVA with ritonavir in patients taking quetiapine: Consider alternative antiretroviral therapy to avoid increases in quetiapine drug exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring. Initiation of quetiapine in patients taking LEXIVA with ritonavir: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.
Lurasidone ↑Lurasidone LEXIVA: If coadministration is necessary, reduce the lurasidone dose. Refer to the lurasidone prescribing information for concomitant use with moderate CYP3A4 inhibitors. LEXIVA/ritonavir: Use of lurasidone is contraindicated.
Benzodiazepines: Alprazolam, clorazepate, diazepam, flurazepam ↑Benzodiazepines Clinical significance is unknown. A decrease in benzodiazepine dose may be needed.
Calcium channel blockers: Diltiazem, felodipine, nifedipine, nicardipine, nimodipine, verapamil, amlodipine, nisoldipine, isradipine ↑Calcium channel blockers Use with caution. Clinical monitoring of patients is recommended.
Corticosteroid: Dexamethasone ↓Amprenavir Use with caution. LEXIVA may be less effective due to decreased amprenavir plasma concentrations.
Endothelin-receptor antagonists: Bosentan ↑Bosentan Coadministration of bosentan in patients on LEXIVA: In patients who have been receiving LEXIVA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Coadministration of LEXIVA in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of LEXIVA. After at least 10 days following the initiation of LEXIVA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Histamine H2-receptor antagonists: Cimetidine, famotidine, nizatidine, ranitidinea LEXIVA: ↓Amprenavir LEXIVA/ritonavir: Interaction not evaluated Use with caution. LEXIVA may be less effective due to decreased amprenavir plasma concentrations.
HMG-CoA reductase inhibitors: Atorvastatina ↑Atorvastatin Titrate atorvastatin dose carefully and use the lowest necessary dose; do not exceed atorvastatin 20 mg/day.
Immunosuppressants: Cyclosporine, tacrolimus, sirolimus ↑Immunosuppressants Therapeutic concentration monitoring is recommended for immunosuppressant agents.
Inhaled beta-agonist: Salmeterol ↑Salmeterol Concurrent administration of salmeterol with LEXIVA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.
Inhaled/nasal steroid: Fluticasone LEXIVA: ↑Fluticasone LEXIVA/ritonavir: ↑Fluticasone Use with caution. Consider alternatives to fluticasone, particularly for long-term use. May result in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression have been reported during postmarketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone. Coadministration of fluticasone and LEXIVA/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.
Narcotic analgesic: Methadone ↓Methadone Data suggest that the interaction is not clinically relevant; however, patients should be monitored for opiate withdrawal symptoms.
Oral contraceptives: Ethinyl estradiol/norethindronea LEXIVA: ↓Amprenavir ↓Ethinyl estradiol LEXIVA/ritonavir: ↓Ethinyl estradiol Alternative methods of non-hormonal contraception are recommended. May lead to loss of virologic response.a Increased risk of transaminase elevations. No data are available on the use of LEXIVA/ritonavir with other hormonal therapies, such as hormone replacement therapy (HRT) for postmenopausal women.
PDE5 inhibitors: Sildenafil, tadalafil, vardenafil ↑Sildenafil ↑Tadalafil ↑Vardenafil May result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH):
Proton pump inhibitors: Esomeprazolea, lansoprazole, omeprazole, pantoprazole, rabeprazole LEXIVA: ↔Amprenavir ↑Esomeprazole LEXIVA/ritonavir: ↔Amprenavir ↔Esomeprazole Proton pump inhibitors can be administered at the same time as a dose of LEXIVA with no change in plasma amprenavir concentrations.
Tricyclic antidepressants: Amitriptyline, imipramine ↑Tricyclics Therapeutic concentration monitoring is recommended for tricyclic antidepressants.


Table name:
Increased Risk of Myopathy/Rhabdomyolysis (2, 5.1, 7, 12.3)
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
Lopinavir plus ritonavir Use lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) Do not exceed 40 mg atorvastatin daily


Table name: Drugs That Interfere with HemostasisClinical Impact:• Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.Intervention:Monitor patients with concomitant use of VOLTAREN® GEL with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].AspirinClinical Impact:Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].Intervention:Concomitant use of VOLTAREN® GEL and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. VOLTAREN® GEL is not a substitute for low dose aspirin for cardiovascular protection.ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-BlockersClinical Impact:• NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.Intervention:• During concomitant use of VOLTAREN® GEL and ACE-inhibitors, ARBs, or beta- blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of VOLTAREN® GEL and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.DiureticsClinical Impact:Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.Intervention:During concomitant use of VOLTAREN® GEL with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].DigoxinClinical Impact:The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.Intervention:During concomitant use of VOLTAREN® GEL and digoxin, monitor serum digoxin levels.LithiumClinical Impact:NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.During concomitant use of VOLTAREN® GEL and lithium, monitor patients for signs of lithium toxicity.MethotrexateClinical Impact:Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).Intervention:During concomitant use of VOLTAREN® GEL and methotrexate, monitor patients for methotrexate toxicity.CyclosporineClinical Impact:Concomitant use of VOLTAREN® GEL and cyclosporine may increase cyclosporine's nephrotoxicity.Intervention:During concomitant use of VOLTAREN® GEL and cyclosporine, monitor patients for signs of worsening renal function.NSAIDs and SalicylatesClinical Impact:Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].Intervention:The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended.PemetrexedClinical Impact:Concomitant use of VOLTAREN® GEL and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).Intervention:During concomitant use of VOLTAREN® GEL and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and Gl toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
 
 
   
 
 
 
 
 
 
   
 
 
         
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
Intervention:
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
     


Table name:
Table 2. Clinically Significant Drug Interactions with Diclofenac
  Drugs That Interfere with Hemostasis
  Clinical Impact:   •Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. •Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
  Intervention:  Monitor patients with concomitant use of diclofenac sodium delayed-release tablets with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS: Hematologic Toxicity ).
  Aspirin
  Clinical Impact:  Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation ).
  Intervention:  Concomitant use of diclofenac sodium delayed-release tablets and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS: Hematologic Toxicity ). Diclofenac sodium delayed-release tablets are not a substitute for low dose aspirin for cardiovascular protection.
  ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
  Clinical Impact:   •NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). •In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
  Intervention:   •During concomitant use of diclofenac sodium delayed-release tablets and ACE-inhibitors, ARBs, or beta- blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. •During concomitant use of diclofenac sodium delayed-release tablets and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS: Renal Toxicity and Hyperkalemia ). •When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
  Diuretics
  Clinical Impact:  Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
  Intervention:  During concomitant use of diclofenac sodium delayed-release tablets with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS: Renal Toxicity and Hyperkalemia ).
  Digoxin
  Clinical Impact:  The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
  Intervention:  During concomitant use of diclofenac sodium delayed-release tablets and digoxin, monitor serum digoxin levels.
  Lithium
  Clinical Impact:  NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
  Intervention:  During concomitant use of diclofenac sodium delayed-release tablets and lithium, monitor patients for signs of lithium toxicity.
  Methotrexate
  Clinical Impact:  Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
  Intervention:  During concomitant use of diclofenac sodium delayed-release tablets and methotrexate, monitor patients for methotrexate toxicity.
  Cyclosporine
  Clinical Impact:  Concomitant use of diclofenac sodium delayed-release tablets and cyclosporine may increase cyclosporine’s nephrotoxicity.
  Intervention:  During concomitant use of diclofenac sodium delayed-release tablets and cyclosporine, monitor patients for signs of worsening renal function.
  NSAIDs and Salicylates
  Clinical Impact:  Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation ).
  Intervention:  The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended.
  Pemetrexed
  Clinical Impact:  Concomitant use of diclofenac sodium delayed-release tablets and pemetrexed may increase the risk of pemetrexed‑ associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
  Intervention:  During concomitant use of diclofenac sodium delayed-release tablets and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
  CYP2C9 Inhibitors or Inducers:
  Clinical Impact:  Diclofenac is metabolized by cytochrome P450 enzymes, predominantly by CYP2C9. Co-administration of diclofenac with CYP2C9 inhibitors (e.g. voriconazole) may enhance the exposure and toxicity of diclofenac whereas co‑administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of diclofenac.
  Intervention:  A dosage adjustment may be warranted when diclofenac is administered with CYP2C9 inhibitors or inducers (see CLINICAL PHARMACOLOGY: Pharmacokinetics ).


Table name:
Drugs That Interfere with Hemostasis
Clinical Impact: Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of diclofenac sodium topical gel with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].
Intervention: Concomitant use of diclofenac sodium topical gel and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. Diclofenac sodium topical gel is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol) In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: During concomitant use of diclofenac sodium topical gel and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of diclofenac sodium topical gel and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of diclofenac sodium topical gel with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Digoxin
Clinical Impact: The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of diclofenac sodium topical gel and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of diclofenac sodium topical gel and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of diclofenac sodium topical gel and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of diclofenac sodium topical gel and cyclosporine may increase cyclosporine's nephrotoxicity.
Intervention: During concomitant use of diclofenac sodium topical gel and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention: The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of diclofenac sodium topical gel and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of diclofenac sodium topical gel and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and Gl toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.


Table name:
Concomitant Drug Name or Drug Class
Clinical Rationale
Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine)
The concomitant use of aripiprazole tablets with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole tablets alone [see CLINICAL PHARMACOLOGY ( 12.3)].
With concomitant use of aripiprazole tablets with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole tablets dosage [see DOSAGE AND ADMINISTRATION ( 2.7)].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)
The concomitant use of aripiprazole tablets and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole tablets alone [see CLINICAL PHARMACOLOGY ( 12.3)].
With concomitant use of aripiprazole tablets with a strong CYP3A4 inducer, consider increasing the aripiprazole tablets dosage [see DOSAGE AND ADMINISTRATION ( 2.7)].
 
Antihypertensive Drugs
Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.
Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS ( 5.8)].
 
 
 
Benzodiazepines (e.g., lorazepam)
The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that
observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS ( 5.7)]
Monitor sedation and blood pressure. Adjust dose accordingly.


Table name:
Effects on Steady-State Fexofenadine Pharmacokinetics After 7 Days of Co-Administration with Fexofenadine Hydrochloride 120 mg Every 12 Hours (two times the recommended twice daily dose) in Healthy Volunteers (n=24)
Concomitant Drug Cmax SS
(Peak plasma concentration)
AUCSS(0–12h)
(Extent of systemic exposure)
Erythromycin
(500 mg every 8 hrs)
+82% +109%
Ketoconazole
(400 mg once daily)
+135% +164%


Table name:
Table 4 Established and Other Potentially SignificantThis table is not all inclusive. Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction
Concomitant Drug Class: Drug Name Effect Clinical Comment
Antiretroviral agents
Protease inhibitor:
  atazanavir
↓atazanavir concentration
↑ tenofovir concentration
Coadministration of atazanavir with ATRIPLA is not recommended. Coadministration of atazanavir with either efavirenz or tenofovir DF decreases plasma concentrations of atazanavir. The combined effect of efavirenz plus tenofovir DF on atazanavir plasma concentrations is not known. Also, atazanavir has been shown to increase tenofovir concentrations. There are insufficient data to support dosing recommendations for atazanavir or atazanavir/ritonavir in combination with ATRIPLA.
Protease inhibitor:
  fosamprenavir calcium
↓ amprenavir concentration Fosamprenavir (unboosted): Appropriate doses of fosamprenavir and ATRIPLA with respect to safety and efficacy have not been established.
 
Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when ATRIPLA is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when ATRIPLA is administered with fosamprenavir plus ritonavir twice daily.
Protease inhibitor:
  indinavir
↓ indinavir concentration The optimal dose of indinavir, when given in combination with efavirenz, is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to efavirenz.
Protease inhibitor:
  lopinavir/ritonavir
↓ lopinavir concentration
↑ tenofovir concentration
A dose increase of lopinavir/ritonavir to 600/150 mg (3 tablets) twice daily may be considered when used in combination with efavirenz in treatment-experienced patients where decreased susceptibility to lopinavir is clinically suspected (by treatment history or laboratory evidence). Patients should be monitored for tenofovir-associated adverse reactions. ATRIPLA should be discontinued in patients who develop tenofovir-associated adverse reactions.
Protease inhibitor:
  ritonavir
↑ ritonavir concentration
↑ efavirenz concentration
When ritonavir 500 mg every 12 hours was coadministered with efavirenz 600 mg once daily, the combination was associated with a higher frequency of adverse clinical experiences (e.g., dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when ATRIPLA is used in combination with ritonavir.
Protease inhibitor:
  saquinavir
↓ saquinavir concentration Should not be used as sole protease inhibitor in combination with ATRIPLA.
NRTI:
  didanosine
↑ didanosine concentration Higher didanosine concentrations could potentiate didanosine-associated adverse reactions, including pancreatitis and neuropathy. In adults weighing >60 kg, the didanosine dose should be reduced to 250 mg if coadministered with ATRIPLA. Data are not available to recommend a dose adjustment of didanosine for patients weighing <60 kg. Coadministration of ATRIPLA and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse reactions. For additional information, please consult the Videx / Videx EC (didanosine) prescribing information.
Other agents
Anticoagulant:
  warfarin
↑ or ↓ warfarin concentration Plasma concentrations and effects potentially increased or decreased by efavirenz.
Anticonvulsants:
  carbamazepine
↓ carbamazepine concentration
↓ efavirenz concentration
There are insufficient data to make a dose recommendation for ATRIPLA. Alternative anticonvulsant treatment should be used.
  phenytoin
  phenobarbital
↓ anticonvulsant concentration
↓ efavirenz concentration
Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted.
Antidepressant:
  sertraline
↓ sertraline concentration Increases in sertraline dose should be guided by clinical response.
Antifungals:
  itraconazole
↓ itraconazole concentration
↓ hydroxy-itraconazole concentration
Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered.
  ketoconazole ↓ ketoconazole concentration Drug interaction studies with ATRIPLA and ketoconazole have not been conducted. Efavirenz has the potential to decrease plasma concentrations of ketoconazole.
Anti-infective:
  clarithromycin
↓ clarithromycin concentration
↑ 14-OH metabolite concentration
Clinical significance unknown. In uninfected volunteers, 46% developed rash while receiving efavirenz and clarithromycin. No dose adjustment of ATRIPLA is recommended when given with clarithromycin. Alternatives to clarithromycin, such as azithromycin, should be considered. Other macrolide antibiotics, such as erythromycin, have not been studied in combination with ATRIPLA.
Antimycobacterial:
  rifabutin
↓ rifabutin concentration Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week.
Antimycobacterial:
  rifampin
↓ efavirenz
concentration
Clinical significance of reduced efavirenz concentration is unknown. Dosing recommendations for concomitant use of ATRIPLA and rifampin have not been established.
Calcium channel blockers:
  diltiazem
↓ diltiazem concentration
↓ desacetyl diltiazem concentration
↓ N-monodes-methyl diltiazem concentration
Diltiazem dose adjustments should be guided by clinical response (refer to the prescribing information for diltiazem). No dose adjustment of ATRIPLA is necessary when administered with diltiazem.
  Others (e.g., felodipine, nicardipine, nifedipine, verapamil) ↓ calcium channel blocker No data are available on the potential interactions of efavirenz with other calcium channel blockers that are substrates of CYP3A. The potential exists for reduction in plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response (refer to the prescribing information for the calcium channel blocker).
HMG-CoA reductase inhibitors:
  atorvastatin
  pravastatin
  simvastatin
↓ atorvastatin concentration
↓ pravastatin concentration
↓ simvastatin concentration
Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased with efavirenz. Consult the prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose.
Hormonal contraceptives:
Oral:
  Ethinyl
  estradiol/Norgestimate
↓ active metabolites of norgestimate A reliable method of barrier contraception must be used in addition to hormonal contraceptives. Efavirenz had no effect on ethinyl estradiol concentrations, but progestin levels (norelgestromin and levonorgestrel) were markedly decreased. No effect of ethinyl estradiol/norgestimate on efavirenz plasma concentrations was observed.
Implant:
  Etonogestrel
↓ etonogestrel A reliable method of barrier contraception must be used in addition to hormonal contraceptives. The interaction between etonogestrel and efavirenz has not been studied. Decreased exposure of etonogestrel may be expected. There have been postmarketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients.
Immunosuppressants:
  Cyclosporine, tacrolimus, sirolimus, and others metabolized by CYP3A
↓ immuno-suppressant Decreased exposure of the immunosuppressant may be expected due to CYP3A induction by efavirenz. These immunosuppressants are not anticipated to affect exposure of efavirenz. Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with ATRIPLA.
Narcotic analgesic:
  methadone
↓ methadone concentration Coadministration of efavirenz in HIV-1 infected individuals with a history of injection drug use resulted in decreased plasma levels of methadone and signs of opiate withdrawal. Methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms. Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms.


Table name:
Table 18. Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
*Change relative to reference
Coadministered Drug
 
Dosing Schedule
Effect on Active Moiety
(Risperidone + 9- Hydroxy-
Risperidone (Ratio*)
Risperidone Dose
Recommendation
Coadministered Drug
Risperidone
AUC
Cmax
Enzyme (CYP2D6) inhibitors
 
 
 
 
Fluoxetine
20 mg/day
2 or 3 mg twice daily
1.4
1.5

Re-evaluate dosing.
Do not exceed 8 mg/day
Paroxetine
10 mg/day
4 mg/day
1.3
-

Re-evaluate dosing.
Do not exceed 8 mg/day
20 mg/day
4 mg/day
1.6
-
40 mg/day
4 mg/day
1.8
-
Enzyme (CYP3A/ PgP inducers) Inducers
 
 
 
 
 
Carbamazepine
573 ± 168 mg/day
 
3 mg twice daily
 
0.51
 
0.55
 

Titrate dose upwards.
Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) inhibitors
 
 
 
 
 
Ranitidine
150 mg twice daily
1 mg single dose
1.2
1.4
Dose adjustment not needed
Cimetidine
400 mg twice daily
1 mg single dose
1.1
1.3
Dose adjustment not needed
Erythromycin
500 mg four times daily
1 mg single dose
1.1
0.94
Dose adjustment not needed
Other Drugs
 
 
 
 
 
Amitriptyline
50 mg twice daily
3 mg twice daily
1.2
1.1
Dose adjustment not Needed


Table name:
DRUG DISCRIPTION OF INTERACTION
Heparin Salicylate decreases platelet adhesiveness and inteferes with hemostasis in heparin treated patients.
Pyrazinamide Inhibits pyrazinamide induced hyperuricemia.
Uricosuric Agents Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited.


Table name:
Drugs that Affect Renal Function A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDS], COX-2 inhibitors may impair the excretion of digoxin.
Antiarrthymics Dofetilide Concomitant administration with digoxin was associated with a higher rate of torsades de pointes
Sotalol Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
Dronedarone Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone Analog Teriparatide Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement Thyroid Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics Epinephrine
Norepinephrine     
Dopamine
Can increase the risk of cardiac arrhythmias
Neuromuscular Blocking Agents      Succinylcholine May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.
Supplements Calcium If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.


Table name:
Table II. Clinically significant drug interactions with theophylline.Refer to PRECAUTIONS, Drug Interactions for further information regarding table.
 Drug  Type of Interaction  EffectAverage effect on steady-state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.
 Adenosine  Theophylline blocks adenosine receptors.  Higher doses of adenosine may be required to achieve desired effect.
 Alcohol  A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours  30% increase
 Allopurinol  Decreases theophylline clearance at allopurinol doses ≥ 600 mg/day  25% increase
 Aminoglutethimide  Increases theophylline clearance by induction of microsomal enzyme activity.  25% decrease
 Carbamazepine  Similar to aminoglutethimide.  30% decrease
 Cimetidine  Decreases theophylline clearance by inhibiting cytochrome P450 1A2.  70% increase
 Ciprofloxacin  Similar to cimetidine.  40% increase
 Clarithromycin  Similar to erythromycin.  25% increase
 Diazepam  Benzodiazepines increase CNS concentratrions of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors.  Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
 Disulfiram  Decreases theophylline clearance by inhibiting hydroxylation and demethylation.  50% increase
 Enoxacin  Similar to cimetidine.  300% increase
 Ephedrine  Synergistic CNS effects  Increased frequency of nausea, nervousness, and insomnia.
 Erythromycin  Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3.  35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
 Estrogen  Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance in unknown.  30% increase
 Flurazepam  Similar to diazepam.  Similar to diazepam.
 Fluvoxamine  Similar to cimetidine.  Similar to cimetidine.
 Halothane  Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines.  Increased risk of ventricular arrhythmias.
 Interferon, human recombinant alpha-A  Decreases theophylline clearance.  100% increase
 Isoproterenol (IV)  Increase theophylline clearance.  20% increase
 Ketamine  Pharmacologic  May lower theophylline seizure threshold.
 Lithium  Theophylline increases renal lithium clearance.  Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
 Lorazepam  Similar to diazepam.  Similar to diazepam.
 Methotrexate (MTX)  Decreases theophylline clearance.  20% increase after low dose MTX, higher dose MTX may have a greater effect.
 Mexiletine  Similar to disulfiram.  80% increase
 Midazolam  Similar to diazepam.  Similar to diazepam.
 Moricizine  Increases theophylline clearance.  25% increase
 Pancuronium  Theophylline may antagonize non-depolarizing neuromuscular blocking effects;possibly due to phosphodiesterase inhibition.  Larger dose of pancuronium may be required to achieve neuromuscular blockade.
 Pentoxifylline  Decreases theophylline clearance.  30% increase
 Phenobarbital (PB)  Similar to aminoglutethimide.  25% decrease after two weeks of concurrent PB.
 Phenytoin  Phenytoin increases theophylline clearance by increasing microsomal enzyme activity.  Serum theophylline and phenytoin concentrations decrease about 40%.
 Propafenone  Decreases theophylline clearance and pharmacologic interaction.  40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
 Propranolol  Similar to cimetidine and pharmacologic interaction.  100% increase Beta-2 blocking effect may decrease efficacy of theophylline.
 Rifampin  Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity.  20-40% decrease
 Sulfinpyrazone  Increase theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline.  20% increase
 Tacrine  Similar to cimetidine, also increases renal clearance of theophylline.  90% increase
 Thiabendazole  Decreases theophylline clearance.  190% increase
 Ticlopidine  Decreases theophylline clearance.  60% increase
 Troleandomycin  Similar to erythromycin.  33-100% increase depending on troleandomycin dose.
 Verapamil  Similar to disulfiram.  20% increase


Table name:
Table 3: Drugs that Can Increase the Risk of Bleeding
 Drug Class  Specific Drugs
 Anticoagulants  argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
 Antiplatelet Agents  aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
 Nonsteroidal Anti-Inflammatory Agents  celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
 Serotonin Reuptake Inhibitors  citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
Table 7:  Summary of AED Interactions with Oxcarbazepine
1nc denotes a mean change of less than 10%
2Pediatrics
3Mean increase in adults at high oxcarbazepine doses
AED
Coadministered
Dose of AED
(mg/day)
Oxcarbazepine Dose
(mg/day)
Influence of
Oxcarbazepine on AED
Concentration
(Mean Change,
90% Confidence
Interval)
Influence of
AED on MHD
Concentration
(Mean Change,
90% Confidence
Interval)
Carbamazepine
400 to 2000
900
nc1
40% decrease
[CI: 17% decrease,
57% decrease]
Phenobarbital
100 to150
600 to 1800
14% increase
[CI: 2% increase,
24% increase]
25% decrease
[CI: 12% decrease,
51% decrease]
Phenytoin
250 to 500
600 to 1800
>1200 to 2400
nc1,2
up to 40%
increase3
[CI: 12% increase,
60% increase]
30% decrease
[CI: 3% decrease,
48% decrease]
Valproic acid
400 to 2800
600 to 1800
nc1
18% decrease
[CI: 13% decrease,
40% decrease]
Lamotrigine
200
1200
nc1
nc1


Table name:
Interacting  Agents 
Prescribing  Recommendations 
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, 
posaconazole, voriconazole, erythromycin, clarithromycin, 
telithromycin, HIV protease inhibitors, boceprevir, telaprevir, 
nefazodone, cobicistatcontaining products), gemfibrozil, 
cyclosporine, danazol 
 Contraindicated with simvastatin 
Verapamil, diltiazem, dronedarone
Do not exceed 10 mg simvastatin daily 
Amiodarone, amlodipine, ranolazine
Do not exceed 20 mg simvastatin daily 
Lomitapide
For patients with HoFH, do not exceed 
20 mg simvastatin dailyFor patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice 
Avoid grapefruit juice  


Table name:
Table 8: Effect of Voriconazole on Pharmacokinetics of Other Drugs [see Clinical Pharmacology (12.3)]
* Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects
** Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects
*** Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for 4 days voriconazole to subjects receiving a methadone maintenance dose (30 to 100 mg q24h)
**** Non-Steroidal Anti-Inflammatory Drug
***** Non-Nucleoside Reverse Transcriptase Inhibitors
Drug/Drug Class
(Mechanism of Interaction by Voriconazole)
Drug Plasma Exposure
(Cmax and AUC τ )
Recommendations for Drug Dosage Adjustment/Comments
Sirolimus*
(CYP3A4 Inhibition)
Significantly Increased
Contraindicated
Rifabutin*
(CYP3A4 Inhibition)
Significantly Increased
Contraindicated
Efavirenz (400 mg q24h)**
(CYP3A4 Inhibition)
 
Efavirenz (300 mg q24h)**
(CYP3A4 Inhibition)
Significantly Increased
 
 
Slight Increase in AUCτ
Contraindicated
 
 
When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)**(CYP3A4 Inhibition)
 
 
Low-dose Ritonavir (100 mg q12h)**
No Significant Effect of Voriconazole on Ritonavir Cmax or AUCτ
 
 
Slight Decrease in Ritonavir Cmax and AUCτ
Contraindicated because of significant reduction of voriconazole Cmax and AUCτ
 
Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole Cmax and AUCτ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine
(CYP3A4 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased
Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids
(CYP450 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased
Contraindicated
Cyclosporine*
(CYP3A4 Inhibition)
AUCτ Significantly Increased; No Significant Effect on Cmax
When initiating therapy with voriconazole in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity.  When voriconazole is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
Methadone*** (CYP3A4 Inhibition)
Increased
Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl (CYP3A4 Inhibition)
Increased
Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7) ]
Alfentanil (CYP3A4 Inhibition)
Significantly Increased
Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with voriconazole. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [see Drug Interactions (7) ].
Oxycodone (CYP3A4 Inhibition)
Significantly Increased
Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7) ].
NSAIDs**** including. ibuprofen and diclofenac
 
(CYP2C9 Inhibition)
Increased
Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed [see Drug Interactions (7) ].
Tacrolimus*
(CYP3A4 Inhibition)
Significantly Increased
When initiating therapy with voriconazole in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels.  Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazole is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin*
(CYP2C9 Inhibition)
Significantly Increased
Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)**
Increased
Monitoring for adverse events related to oral contraceptives is recommended during coadministration.
Warfarin*
(CYP2C9 Inhibition)
Prothrombin Time Significantly Increased
Monitor PT or other suitable anti- coagulation tests. Adjustment of warfarin dosage may be needed.
Omeprazole*
(CYP2C19/3A4 Inhibition)
Significantly Increased
When initiating therapy with voriconazole in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)
In Vivo Studies Showed No Significant Effects on Indinavir Exposure
 
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)
No dosage adjustment for indinavir when coadministered with voriconazole
 
Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors
Other NNRTIs*****
(CYP3A4 Inhibition)
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the  Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity related to NNRTI
Benzodiazepines
(CYP3A4 Inhibition)
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.
HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition)
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers
(CYP3A4 Inhibition)
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased
Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia.  Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids
(CYP3A4 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased
Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids.  Adjustment of vinca alkaloid dosage may be needed.
Everolimus
(CYP3A4 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased
Concomitant administration of voriconazole and everolimus is not recommended.


Table name:
Table 6. Established and Other Potentially Significant Drug Interactions with Ganciclovir
Name of the Concomitant Drug Change in the Concentration of Ganciclovir or Concomitant Drug Clinical Comment
 Didanosine  ↑ Didanosine Patients should be closely monitored for didanosine toxicity.
 Zidovudine  ↓ Ganciclovir
 ↑ Zidovudine                                                                                                                                                                                                     
Dose reduction or interruption may be needed because both zidovudine and ganciclovir have the potential to cause neutropenia and anemia. Monitor with frequent tests of white blood cell counts with differential and hemoglobin levels.
 Probenecid  ↑ Ganciclovir GANCICLOVIR INJECTION dose may need to be reduced. Monitor for evidence of ganciclovir toxicity.
 Imipenem-cilastatin  Unknown Coadministration with imipenem-cilastatin is not recommended because generalized seizures have been reported in patients who received ganciclovir and imipenem-cilastatin.
 Cyclosporine or amphotericin B  Unknown Monitor renal function when GANCICLOVIR INJECTION is co-administered with cyclosporine or amphotericin B because of potential increase in serum creatinine [see Warnings and Precautions (5.2)].
Dapsone, pentamidine, flucytosine, vincristine, vinblastine, adriamycin, amphotericin B, trimethoprim/sulfamethoxazole combinations or other nucleoside analogues  Unknown Co-administration with GANCICLOVIR INJECTION should be considered only if the potential benefits are judged to outweigh the risks because of potential additive toxicity.


Table name:
Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
  Coadministered Drug   Dosing Schedule   Effect on Active Moiety(Risperidone + 9- Hydroxy- Risperidone (Ratio*)   Risperidone DoseRecommendation
    Coadministered Drug   Risperidone   AUC   Cmax  
 Enzyme (CYP2D6)Inhibitors          
 Fluoxetine  20 mg/day  2 or 3 mg twice daily  1.4  1.5  Re-evaluate dosing. Donot exceed 8 mg/day
 Paroxetine  10 mg/day  4 mg/day  1.3  -  
   20 mg/day  4 mg/day  1.6  -  
   40 mg/day  4 mg/day  1.8  -  Re-evaluate dosing. Do not exceed 8 mg/day
 Enzyme (CYP3A/PgP inducers)Inducers          
 Carbamazepine  573 ± 168 mg/day  3 mg twice daily  0.51  0.55  Titrate dose upwards.Do not exceed twice the patient’s usual dose
 Enzyme (CYP3A)Inhibitors          
 Ranitidine  150 mg twice daily  1 mg single dose  1.2  1.4  Dose adjustment not needed
 Cimetidine  400 mg twice daily  1 mg single dose  1.1  1.3  Dose adjustment not needed
 Erythromycin  500 mg four times daily  1 mg single dose  1.1  0.94  Dose adjustment not needed
           
 Other Drugs          
 Amitriptyline  50 mg twice daily  3 mg twice daily  1.2  1.1  Dose adjustment not needed


Table name:
Antibiotics Antineoplastics Anti-inflammatory Drugs Gastrointestinal Agents
ciprofloxacin melphalan Azapropazon cimetidine
gentamicin   Colchicine ranitidine
tobramycin Antifungals Diclofenac  
vancomycin amphotericin B Naproxen Immunosuppressives
trimethoprim with sulfamethoxazole ketoconazole Sulindac tacrolimus
       
      Other Drugs
      fibric acid derivatives
(e.g., bezafibrate, fenofibrate)
      methotrexate


Table name:
Table 2. Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T4 and T3 serum transport - but FT4 concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors
(SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 3. Comparison of Clopidogrel Active Metabolite Exposure and Platelet Inhibition with and without Proton Pump Inhibitors, Omeprazole and Pantoprazole
 
% Change from Plavix (300 mg/75 mg) alone
Plavix plus Cmax (ng/mL) AUC Platelet InhibitionInhibition of platelet aggregation with 5 mcM ADP (%)
Day 1 Day 5 Day 1 Day 5AUC at Day 5 is AUC0–24 Day 1 Day 5
OmeprazoleSimilar results seen when Plavix and omeprazole were administered 12 hours apart. 80 mg ↓46% ↓42% ↓45% ↓40% ↓39% ↓21%
Pantoprazole 80 mg ↓24% ↓28% ↓20% ↓14% ↓15% ↓11%


Table name:
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. The depressant effects of morphine are potentiated by the presence of other CNS depressants. Use of neuroleptics in conjunction with neuraxial morphine may increase the risk of respiratory depression.
Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.5)].
Examples: Alcohol, benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, psychotropic drugs, antihistamines, neuroleptics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue INFUMORPH if serotonin syndrome is suspected.
Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.9)].
Intervention:   Do not use INFUMORPH in patients taking MAOIs or within 14 days of stopping such treatment. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses of other opioids (such as oxycodone, hydrocodone, oxymorphone, hydrocodone, or buprenorphine) to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
Examples: phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:  May reduce the analgesic effect of INFUMORPH and/or precipitate withdrawal symptoms.
Intervention:  Avoid concomitant use.
Examples:  Butorphanol, nalbuphine, pentazocine, buprenorphine.
Muscle Relaxants
Clinical Impact: Morphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of INFUMORPH and/or the muscle relaxant as necessary.
Diuretics  
Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation,which may lead to paralytic ileus.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when INFUMORPH is used concomitantly with anticholinergic drugs.


Table name:
Table 2: Clinically Significant Drug Interactions with Oxaprozin Drugs That Interfere with Hemostasis
Clinical Impact: Oxaprozin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of oxaprozin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of oxaprozin with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11 )].
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].
Intervention: Concomitant use of oxaprozin and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. Oxaprozin is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: During concomitant use of oxaprozin and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of oxaprozin and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of oxaprozin with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)]. 
Digoxin
Clinical Impact: The concomitant use of oxaprozin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of oxaprozin and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of oxaprozin and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction) because NSAID administration may result in increased plasma levels of methotrexate, especially in patients receiving high doses of methotrexate.
Intervention: During concomitant use of oxaprozin and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of oxaprozin and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of oxaprozin and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of oxaprozin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention: The concomitant use of oxaprozin with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of oxaprozin and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of oxaprozin and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Corticosteroids  
Clinical Impact: Concomitant use of corticosteroids with oxaprozin may increase the risk of GI ulceration or bleeding.
Intervention: Monitor patients with concomitant use of oxaprozin with corticosteroids for signs of bleeding [see Warnings and Precautions (5.2)].
Glyburide  
Clinical Impact: While oxaprozin does alter the pharmacokinetics of glyburide, coadministration of oxaprozin to type II non-insulin dependent diabetic patients did not affect the area under the glucose concentration curve nor the magnitude or duration of control.
Intervention: During concomitant use of oxaprozin and glyburide, monitor patient’s blood glucose in the beginning phase of cotherapy.


Table name:
Factors
Dosage Adjustment of Aripiprazole tablets
Known CYP2D6 Poor Metabolizers
Administer half of usual dose
KnownCYP2D6Poor Metabolizersand strongCYP3A4 inhibitors
Administer a quarter of usualdose
StrongCYP2D6 or CYP3A4inhibitors
Administerhalf of usual dose
StrongCYP2D6andCYP3A4 inhibitors
Administer a quarter of usualdose
StrongCYP3A4inducers
Double usual doseover 1 to 2 weeks


Table name:
AED Coadministered AED Concentration Topiramate Concentration
Phenytoin
NC or 25% increasePlasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
48% decrease


Carbamazepine (CBZ)
NC
40% decrease
CBZ epoxideIs not administered but is an active metabolite of carbamazepine.
NC
NE
Valproic acid
11% decrease
14% decrease
Phenobarbital
NC
NE
Primidone
NC
NE
Lamotrigine
NC at TPM doses up to 400 mg/day
13% decrease


Table name:
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel   ↓ lamotrigine    
↓ levonorgestrel
Decreased lamotrigine levels approximately 50%.   Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide ↓ lamotrigine   

? CBZ epoxide
Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
May increase CBZ epoxide levels
Phenobarbital/Primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT) ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine   

? valproate
Increased lamotrigine concentrations slightly more than 2-fold.  
Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
Table 2. Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T4 and T3 serum transport - but FT4 concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors
(SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Specific Drugs Reported
also: diet high in vitamin K
unreliable PT/INR determinations
†Increased and decreased PT/INR responses have been reported.
alcohol†
aminoglutethimide
amobarbital
atorvastatin†
azathioprine
butabarbital
butalbital
carbamazepine
chloral hydrate†
chlordiazepoxide
chlorthalidone
cholestyramine†
clozapine
corticotropin
cortisone
cyclophosphamide†
dicloxacillin
ethchlorvynol
glutethimide
griseofulvin
haloperidol
meprobamate
6-mercaptopurine
methimazole†
moricizine hydrochloride†
nafcillin
paraldehyde
pentobarbital
phenobarbital
phenytoin†
pravastatin†
prednisone†
primidone
propylthiouracil†
raloxifene
ranitidine†
rifampin
secobarbital
spironolactone
sucralfate
trazodone
vitamin C (high dose)
vitamin K
warfarin underdosage


Table name:

albuterol, systemic and inhaled

mebendazole

amoxicillin

medroxyprogesterone

ampicillin, with or without

methylprednisolone

sulbactam

metronidazole

atenolol

metoprolol

azithromycin

nadolol

caffeine, dietary ingestion

nifedipine

cefaclor

nizatidine

co-trimoxazole (trimethoprim and

sulfamethoxazole)

norfloxacin

ofloxacin

diltiazem

omeprazole

dirithromycin

prednisone, prednisolone

enflurane

ranitidine

famotidine

rifabutin

felodipine

roxithromycin

finasteride

Sorbitol (purgative doses do not inhibit

hydrocortisone

theophylline absorption)

isoflurane

sucralfate

isoniazid

terbutaline, systemic

isradipine

terfenadine

influenza vaccine

tetracycline

ketoconazole

tocainide

lomefloxacin

 


Table name:
Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) VIAGRA 25 mg
Supine 7.4 (-0.9, 15.7)
Standing 6.0 (-0.8, 12.8)


Table name:
Factors Dosage Adjustments for Aripiprazole
Known CYP2D6 Poor Metabolizers Administer half of usual dose
Known CYP2D6 Poor Metabolizersand strong CYP3A4 inhibitors Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors Administer half of usual dose
Strong CYP2D6 and CYP3A4inhibitors Administer a quarter of usual dose
Strong CYP3A4 inducers Double usual dose over 1 to 2 weeks


Table name:
Table 1: Clinically Significant Drug Interactions with Morphine Sulfate Injection, (Auto-Injector)
Benzodiazepines and other Central Nervous System (CNS) Depressants
Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.4)].
Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention: If concomitant use is warranted, carefully observe the patient during treatment initiation. Discontinue Morphine Sulfate Injection, (Auto-Injector) if serotonin syndrome is suspected.
Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.6)].
Intervention: Do not use Morphine Sulfate Injection, (Auto-Injector) in patients taking MAOIs or within 14 days of stopping such treatment.
If urgent use of an opioid is necessary, use test doses and frequent titration of small doses of other opioids (such as oxycodone, hydrocodone, oxymorphone, hydrocodone, or buprenorphine) to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
Examples: phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact: May reduce the analgesic effect of Morphine Sulfate Injection, (Auto-Injector) and/or precipitate withdrawal symptoms.
Intervention: Avoid concomitant use.
Examples: butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact: Morphine sulfate may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the frequency of injections of Morphine Sulfate Injection, (Auto-Injector) and/or decrease the dose of the muscle relaxant as necessary.
Diuretics
Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when Morphine Sulfate Injection, (Auto-Injector) is used concomitantly with anticholinergic drugs.


Table name:
Table 3 Clinically Significant Drug Interactions with Meloxicam
Drugs  that  Interfere  with  Hemostasis
Clinical  Impact :
Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.
Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. 
Intervention :
Monitor patients with concomitant use of meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding  [ see  WARNINGS  AND  PRECAUTIONS  ( 5 . 11 )].
Aspirin
Clinical  Impact :
Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone  [ see  WARNINGS  AND  PRECAUTIONS  ( 5 . 2 )].
Intervention :
Concomitant use of meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding  [ see  WARNINGS  AND  PRECAUTIONS  ( 5 . 11 )]. 

Meloxicam is not a substitute for low dose aspirin for cardiovascular protection.
ACE  Inhibitors Angiotensin  Receptor  Blockers or  Beta - Blockers
Clinical  Impact :
NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).
In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention :
During concomitant use of meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.
During concomitant use of meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function  [ see  WARNINGS  AND  PRECAUTIONS  ( 5 . 6 )]. 
When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical  Impact :
Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam.
Intervention :
During concomitant use of meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects  [ see  WARNINGS  AND  PRECAUTIONS  ( 5 . 6 )].
Lithium
Clinical  Impact :
NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis  [ see  CLINICAL  PHARMACOLOGY  ( 12 . 3 )].
Intervention :
During concomitant use of meloxicam and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical  Impact :
Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention :
During concomitant use of meloxicam and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical  Impact :
Concomitant use of meloxicam and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention :
During concomitant use of meloxicam and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs  and  Salicylates
Clinical  Impact :
Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy  [ see  WARNINGS  AND  PRECAUTIONS  ( 5 . 2 )].
Intervention :
The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical  Impact :
Concomitant use of meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention :
During concomitant use of meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.
Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended.


Table name:
Interacting Drug Interaction
Theophylline Serious and fatal reactions. Avoid concomitant use. Monitor serum level ( 7)
Warfarin Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding ( 7)
Antidiabetic agents Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose ( 7)
Phenytoin Monitor phenytoin level ( 7)
Methotrexate Monitor for methotrexate toxicity ( 7)
Cyclosporine May increase serum creatinine. Monitor serum creatinine ( 7)
Multivalent cation-containing products including antacids, metal cations or didanosine Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin ( 7)


Table name:
Table 4 Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table 5 for Magnitude of Interaction.
* The interaction between nevirapine and the drug was evaluated in a clinical study. All other drug interactions shown are predicted.
Drug Name Effect on Concentration of
Nevirapine or Concomitant Drug
Clinical Comment
HIV Antiviral Agents: Protease Inhibitors (PIs)
Atazanavir/Ritonavir*

↓ Atazanavir
↑ Nevirapine

Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures.

Fosamprenavir*

↓ Amprenavir
↑ Nevirapine

Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.

Fosamprenavir/Ritonavir*

↓ Amprenavir

↑ Nevirapine

No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied.

Indinavir*

↓ Indinavir

The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established.

Lopinavir/Ritonavir*

↓Lopinavir

Dosing in adult patients:

A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.

Dosing in pediatric patients:

Please refer to the Kaletra® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.

Nelfinavir*

↓Nelfinavir M8 Metabolite
↓Nelfinavir Cmin

The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established.

Saquinavir/ritonavir

The interaction between nevirapine and saquinavir/ritonavir has not been evaluated

The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.

HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz*

↓ Efavirenz

The appropriate doses of these combinations with respect to safety and efficacy have not been established.

Delavirdine
Etravirine
Rilpivirine

  Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial.

Hepatitis C Antiviral Agents
Boceprevir

Plasma concentrations of boceprevir may be decreased due to induction of CYP3A4/5 by nevirapine.

Nevirapine and boceprevir should not be coadministered because decreases in boceprevir plasma concentrations may result in a reduction in efficacy.

Telaprevir

Plasma concentrations of telaprevir may be decreased due to induction of CYP3A4 by nevirapine and plasma concentrations of nevirapine may be increased due to inhibition of CYP3A4 by telaprevir.

Nevirapine and telaprevir should not be coadministered because changes in plasma concentrations of nevirapine, telaprevir, or both may result in a reduction in telaprevir efficacy or an increase in nevirapine-associated adverse events.

Other Agents
Analgesics:  
Methadone*

↓ Methadone

Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.

Antiarrhythmics:    
Amiodarone, disopyramide, lidocaine

Plasma concentrations may be decreased.

Appropriate doses for this combination have not been established.

Antibiotics:    
Clarithromycin*

↓ Clarithromycin
↑ 14-OH clarithromycin

Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.

Rifabutin*

↑ Rifabutin

Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.

Rifampin*

↓ Nevirapine

Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.

Anticonvulsants:
Carbamazepine, clonazepam, ethosuximide


Plasma concentrations of nevirapine and the anticonvulsant may be decreased.


Use with caution and monitor virologic response and levels of anticonvulsants.

Antifungals:    
Fluconazole*

↑Nevirapine

Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events.

Ketoconazole*

↓ Ketoconazole

Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.

Itraconazole

↓ Itraconazole

Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug.

Antithrombotics:
Warfarin


Plasma concentrations may be increased.


Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.

Calcium channel blockers:
Diltiazem, nifedipine, verapamil


Plasma concentrations may be decreased.


Appropriate doses for these combinations have not been established.

Cancer chemotherapy:
Cyclophosphamide


Plasma concentrations may be decreased.


Appropriate doses for this combination have not been established.

Ergot alkaloids:
Ergotamine


Plasma concentrations may be decreased.


Appropriate doses for this combination have not been established.

Immunosuppressants:
Cyclosporine, tacrolimus, sirolimus


Plasma concentrations may be decreased.


Appropriate doses for these combinations have not been established.

Motility agents:
Cisapride


Plasma concentrations may be decreased.


Appropriate doses for this combination have not been established.

Opiate agonists:
Fentanyl


Plasma concentrations may be decreased.


Appropriate doses for this combination have not been established.

Oral contraceptives:    
Ethinyl estradiol and Norethindrone*

↓ Ethinyl estradiol
↓ Norethindrone

Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended.



Table name:
Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s) Recommendation Comments
Tizanidine Contraindicated Concomitant administration of tizanidine and Ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [ see Contraindications ( 4.2) ]
Theophylline Avoid Use (Plasma Exposure Likely to be Increased and Prolonged) Concurrent administration of Ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate. [See Warnings and Precautions ( 5.6).]
Drugs Known to Prolong QT Interval Avoid Use Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions ( 5.10) and Use in Specific Populations ( 8.5)].
Oral antidiabetic drugs
Use with caution Glucose-lowering effect potentiated Hypoglycemia sometimes severe has been reported when Ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when Ciprofloxacin is co-administered with oral antidiabetic drugs. [See Adverse Reactions ( 6.1).]
Phenytoin
Use with caution Altered serum levels of phenytoin (increased and decreased) To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon Ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of Ciprofloxacin with phenytoin.
Cyclosporine
Use with caution (transient elevations in serum creatinine) Monitor renal function (in particular serum creatinine) when Ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs
Use with caution (Increase in anticoagulant effect) The risk may vary with the underlying infection, age and general status of the patient so that the contribution of Ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of Ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate
Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant Ciprofloxacin therapy is indicated.
Ropinirole
Use with caution
Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after coadministration with Ciprofloxacin [see Warnings and Precautions ( 5.15)].
Clozapine
Use with caution
Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with Ciprofloxacin are advised.
NSAIDs
Use with caution
Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil
Use with caution Two-fold increase in exposure Monitor for sildenafil toxicity ( see Pharmacokinetics 12.3 ).
Duloxetine
Avoid Use
Five-fold increase in duloxetine exposure
If unavoidable, monitor for duloxetine toxicity.
Caffeine/Xanthine
Derivatives
Use with caution
Reduced clearance resulting in elevated levels and prolongation of serum half-life
Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx®
(didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)
Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration. ( 2)].
Decrease Ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid Use with caution (interferes with renal tubular secretion of Ciprofloxacin and increases Ciprofloxacin serum levels) Potentiation of Ciprofloxacin toxicity may occur.


Table name:
Table 18. Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
*Change relative to reference
Coadministered Drug
 
Dosing Schedule
Effect on Active Moiety
(Risperidone + 9- Hydroxy-
Risperidone (Ratio*)
Risperidone Dose
Recommendation
Coadministered Drug
Risperidone
AUC
Cmax
Enzyme (CYP2D6) inhibitors
 
 
 
 
Fluoxetine
20 mg/day
2 or 3 mg twice daily
1.4
1.5

Re-evaluate dosing.
Do not exceed 8 mg/day
Paroxetine
10 mg/day
4 mg/day
1.3
-

Re-evaluate dosing.
Do not exceed 8 mg/day
20 mg/day
4 mg/day
1.6
-
40 mg/day
4 mg/day
1.8
-
Enzyme (CYP3A/ PgP inducers) Inducers
 
 
 
 
 
Carbamazepine
573 ± 168 mg/day
 
3 mg twice daily
 
0.51
 
0.55
 

Titrate dose upwards.
Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) inhibitors
 
 
 
 
 
Ranitidine
150 mg twice daily
1 mg single dose
1.2
1.4
Dose adjustment not needed
Cimetidine
400 mg twice daily
1 mg single dose
1.1
1.3
Dose adjustment not needed
Erythromycin
500 mg four times daily
1 mg single dose
1.1
0.94
Dose adjustment not needed
Other Drugs
 
 
 
 
 
Amitriptyline
50 mg twice daily
3 mg twice daily
1.2
1.1
Dose adjustment not Needed


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
↓ = Decreased (induces lamotrigine glucuronidation).
↑ = Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
Concomitant Drug 
Effect on Concentration of 
Lamotrigine or Concomitant Drug 
Clinical Comment 
Estrogen-containing oral 
contraceptive 
preparations containing 30 mcg 
ethinylestradiol and 150 mcg levonorgestrel 
↓ lamotrigine 

↓ levonorgestrel 
Decreased lamotrigine concentrations approximately 50%. 

Decrease in levonorgestrel component by 19%. 
Carbamazepine and carbamazepine epoxide 
↓ lamotrigine 


? carbamazepine epoxide 
Addition of carbamazepine decreases 
lamotrigine concentration approximately 40%. 
May increase carbamazepine epoxide levels. 
Lopinavir/ritonavir 
↓ lamotrigine 
Decreased lamotrigine concentration approximately 50%. 
Atazanavir/ritonavir 
↓ lamotrigine
Decreased lamotrigine AUC approximately 32%. 
Phenobarbital/Primidone 
↓ lamotrigine 
Decreased lamotrigine concentration
 approximately 40%. 
Phenytoin 
↓ lamotrigine 
Decreased lamotrigine concentration 
approximately 40%. 
Rifampin 
↓ lamotrigine 
Decreased lamotrigine AUC 
approximately 40%. 
Valproate 
↑ lamotrigine

 ? valproate 
Increased lamotrigine concentrations 
slightly more than 2-fold. 
There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.


Table name:
Table 7 Summary of AED Interactions with Oxcarbazepine
1 nc denotes a mean change of less than 10%
2 Pediatrics
3 Mean increase in adults at high oxcarbazepine doses
AED Coadministered Dose of AED (mg/day) Oxcarbazepine
Dose (mg/day)
Influence of Oxcarbazepineon AED Concentration (Mean Change, 90% Confidence Interval) Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine 400 to 2000 900 nc1 40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital 100 to 150 600 to 1800 14% increase [CI: 2% increase, 24% increase] 25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin 250 to 500 600 to 1800 > 1200 to 2400 nc1,2 up to 40% increase3 [CI: 12% increase, 60% increase] 30% decrease [CI: 3% decrease, 48% decrease]
Valproic acid 400 to 2800 600 to 1800 nc1 18% decrease [CI: 13% decrease, 40% decrease]


Table name: Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology (12.3)]. Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see Clinical Pharmacology (12.3)]. There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole.
Table 3: Clinically Relevant Interactions Affecting Drugs Co-Administered with Omeprazole and Interaction with Diagnostics
Antiretrovirals
Clinical Impact:
The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known.
Intervention:
Rilpivirine-containing products: Concomitant use with omeprazole is contraindicated [see Contraindications (4)].
 
Atazanavir: Avoid concomitant use with omeprazole. See prescribing information for atazanavir for dosing information.
 
Nelfinavir: Avoid concomitant use with omeprazole. See prescribing information for nelfinavir.
 
Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities.
 
Other antiretrovirals: See prescribing information for specific antiretroviral drugs.
Warfarin
Clinical Impact:
Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
Intervention:
Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range.
Methotrexate
Clinical Impact:
Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions (5.11)].
Intervention:
A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate.
CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam)
Clopidogrel
Clinical Impact:
Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology (12.3)].
There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel.
Intervention:
Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy [see Warnings and Precautions (5.6)].
Citalopram
Clinical Impact:
Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology (12.3)].
Intervention:
Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.
Cilostazol
Clinical Impact:
Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology (12.3)].
Intervention:
Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.
Phenytoin
Clinical Impact:
Potential for increased exposure of phenytoin.
Intervention:
Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin.
Diazepam
Clinical Impact:
Increased exposure of diazepam [see Clinical Pharmacology (12.3)].
Intervention:
Monitor patients for increased sedation and reduce the dose of diazepam as needed.
Digoxin
Clinical Impact:
Potential for increased exposure of digoxin [see Clinical Pharmacology (12.3)].
Intervention:
Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)
Clinical Impact:
Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
Intervention:
Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF [see Clinical Pharmacology (12.3)].
 
See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact:
Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions.
Intervention:
See Contraindications, Warnings and Precautions  in prescribing information for clarithromycin.
 
See Drug Interactions in prescribing information for amoxicillin.
Tacrolimus
Clinical Impact:
Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.
Intervention:
Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact:
Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions (5.10), Clinical Pharmacology (12.2)].
Intervention:
Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
Interaction with Secretin Stimulation Test
Clinical Impact:
Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention:
Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology (12.2)].
False Positive Urine Tests for THC
Clinical Impact:
There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.
Intervention:
An alternative confirmatory method should be considered to verify positive results.
Other
Clinical Impact:
There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram).
Intervention:
Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole.


Table name:
Table 6 Clinically Important Drug Interactions
  Concomitant Drug Name or Drug Class   Clinical Rationale   Clinical Recommendation
 Tricyclic antidepressants  Increase blood pressure and may counteract clonidine’s hypotensive effects  Monitor blood pressure and adjust as needed
 Antihypertensive drugs  Potentiate clonidine’s hypotensive effects  Monitor blood pressure and adjust as needed
 CNS depressants  Potentiate sedating effects  Avoid use
 Drugs that affect sinus node function or AV node conduction (e.g., digitalis, calcium channel blockers, beta blockers)  Potentiate bradycardia and risk of AV block  Avoid use


Table name:
Table 29: Clinically Important Drug Interactions with Latuda
Strong CYP3A4 Inhibitors
Clinical Impact: Concomitant use of LATUDA with strong CYP3A4 inhibitors increased the exposure of lurasidone compared to the use of LATUDA alone [see Clinical Pharmacology (12.3)].
Intervention: LATUDA should not be used concomitantly with strong CYP3A4 inhibitors [see Contraindications (4)].
Examples: Ketoconazole, clarithromycin, ritonavir, voriconazole, mibefradil
Moderate CYP3A4 Inhibitors
Clinical Impact: Concomitant use of LATUDA with moderate CYP3A4 inhibitors increased the exposure of lurasidone compared to the use of LATUDA alone [see Clinical Pharmacology (12.3)].
Intervention: LATUDA dose should be reduced to half of the original level when used concomitantly with moderate inhibitors of CYP3A4 [see Dosage and Administration (2.6)].
Examples: Diltiazem, atazanavir, erythromycin, fluconazole, verapamil
Strong CYP3A4 Inducers
Clinical Impact: Concomitant use of LATUDA with strong CYP3A4 inducers decreased the exposure of lurasidone compared to the use of LATUDA alone [see Clinical Pharmacology (12.3)].
Intervention: LATUDA should not be used concomitantly with strong CYP3A4 inhibitors [see Contraindications (4)].
Examples: Rifampin, avasimibe, St. John's wort, phenytoin, carbamazepine
Moderate CYP3A4 Inducers
Clinical Impact: Concomitant use of LATUDA with strong CYP3A4 inducers decreased the exposure of lurasidone compared to the use of LATUDA alone [see Clinical Pharmacology (12.3)].
Intervention: LATUDA dose should be increased when used concomitantly with moderate inducers of CYP3A4 [see Dosage and Administration (2.6)].
Examples: Bosentan, efavirenz, etravirine, modafinil, nafcillin


Table name:
Table 3 Clinically Significant Drug Interactions with Meloxicam
Drugs that Interfere with Hemostasis
Clinical Impact: Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ see Warnings and Precautions (5.2)].
Intervention: Concomitant use of meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions (5.11)]. Meloxicam is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, or Beta-Blockers
Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, coadministration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: During concomitant use of meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam.
Intervention: During concomitant use of meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ see Warnings and Precautions (5.6)].
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [ see Clinical Pharmacology (12.3)].
Intervention: During concomitant use of meloxicam and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of meloxicam and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of meloxicam and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of meloxicam and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ see Warnings and Precautions (5.2)].
Intervention: The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended.


Table name:
Concomitant Drug Name or Drug Class Clinical Rationale Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)]. With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin) The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)]. With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Antihypertensive Drugs Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.8) ].
Benzodiazepines (e.g., lorazepam) The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.8) ]. Monitor sedation and blood pressure. Adjust dose accordingly.


Table name:
Interacting  Agents 
Prescribing  Recommendations 
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol
Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone
Do not exceed 10 mg simvastatin daily 
Amiodarone, Amlodipine, ranolazine
Do not exceed 20 mg simvastatin daily 
Grapefruit juice 
Avoid grapefruit juice 


Table name:
Antiretrovirals 
Clinical Impact: The effect of PPI on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir, and nelfinavir) when used concomitantly with rabeprazole may reduce antiviral effect and promote the development of drug resistance. Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with rabeprazole may increase toxicity. There are other antiretroviral drugs which do not result in clinically relevant interactions with rabeprazole.  
Intervention: Rilpivirine-containing products: Concomitant use with Rabeprazole Sodium Delayed-Release Tablets is contraindicated [see Contraindications (4)]. See prescribing information. Atazanavir: See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with Rabeprazole Sodium Delayed-Release Tablets. See prescribing information for nelfinavir. Saquinavir: See the prescribing information for saquinavir and monitor for potential saquinavir toxicities. Other antiretrovirals: See prescribing information.
 Warfarin
Clinical Impact: Increased INR and prothrombin time in patients receiving PPIs, including rabeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death [see Warnings and Precautions (5.2)].
Intervention: Monitor INR and prothrombin time. Dose adjustment of warfarin may be needed to maintain target INR range. See prescribing information for warfarin.
Methotrexate
Clinical Impact: Concomitant use of rabeprazole with methotrexate (primarily at high dose) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of methotrexate with PPIs have been conducted [see Warnings and Precautions (5.9)].
Intervention: A temporary withdrawal of Rabeprazole Sodium Delayed-Release Tablets may be considered in some patients receiving high dose methotrexate administration.
Digoxin
Clinical Impact: Potential for increased exposure of digoxin [see Clinical Pharmacology (12.3)].
Intervention: Monitor digoxin concentrations. Dose adjustment of digoxin may be needed to maintain therapeutic drug concentrations. See prescribing information for digoxin.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole, itraconazole)
Clinical Impact: Rabeprazole can reduce the absorption of drugs due to its effect on reducing intragastric acidity.
Intervention: Mycophenolate mofetil (MMF): Co-administration of PPIs in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving PPIs and MMF. Use Rabeprazole Sodium Delayed-Release Tablets with caution in transplant patients receiving MMF. See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact: Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions.
Intervention: See Contraindications and Warnings and Precautions in prescribing information for clarithromycin. See Drug Interactions in prescribing information for amoxicillin.


Table name:
Interacting Agents Prescribing Recommendations 
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, gemfibrozil, cyclosporine,danazol Contraindicated with simvastatin 
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine  Do not exceed 20 mg simvastatin daily
Grapefruit juice Avoid grapefruit juice


Table name:
Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.*
 albuterol, systemic and inhaled  diltiazem  medroxyprogesterone  roxithromycin
 dirithromycin  methylprednisolone  Sorbitol
(purgative doses do  not inhibit theophylline absorption)
 amoxicillin  enflurane  metronidazole
 ampicillin, with or without sulbactam  famotidine  metoprolol
 felodipine  nadolol
 finasteride  nifedipine
 atenolol  hydrocortisone  nizatidine  sucralfate
 azithromycin  isoflurane  norfloxacin  terbutaline, systemic
 caffeine, dietary   ingestion  isoniazid  ofloxacin  terfenadine
 isradipine  omeprazole  tetracycline
 cefaclor  influenza vaccine  prednisone,
prednisolone
 tocainide
 co-trimoxazole (trimethoprim and sulfamethoxazole)  ketoconazole  
 lomefloxacin  ranitidine  
 mebendazole  rifabutin  
 * Refer to PRECAUTIONS, Drug Interactions for information regarding table.


Table name:
Table 2. Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T4 and T3 serum transport - but FT4 concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors
(SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Interacting Agents Prescribing Recommendations 
Itraconazole, ketoconazole, Posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine,danazol Contraindicated with simvastatin 
Verapamil, diltiazem Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine  Do not exceed 20 mg simvastatin daily
Grapefruit juice Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Table 4. Drug Interactions with PRIFTIN: Dosage Adjustment may be Necessary
Drug Class Examples of Drugs Within Class
Antiarrhythmics Disopyramide, mexiletine, quinidine, tocainide
Antibiotics Chloramphenicol, clarithromycin, dapsone, doxycycline;
Fluoroquinolones (such as ciprofloxacin)
Oral Anticoagulants Warfarin
Anticonvulsants Phenytoin
Antimalarials Quinine
Azole Antifungals Fluconazole, itraconazole, ketoconazole
Antipsychotics Haloperidol
Barbiturates Phenobarbital
Benzodiazepines Diazepam
Beta-Blockers Propanolol
Calcium Channel Blockers Diltiazem, nifedipine, verapamil
Cardiac Glycoside Preparations Digoxin
Corticosteroids Prednisone
Fibrates Clofibrate
Oral Hypoglycemics Sulfonylureas (e.g., glyburide, glipizide)
Hormonal Contraceptives/ Progestins Ethinyl estradiol, levonorgestrel
Immunosuppressants Cyclosporine, tacrolimus
Methylxanthines Theophylline
Narcotic analgesics Methadone
Phophodiesterase-5 (PDE-5) Inhibitors Sildenafil
Thyroid preparations Levothyroxine
Tricyclic antidepressants Amitriptyline, nortriptyline


Table name:
AED  Coadministered
AED  Concentration
Topiramate 
Concentration

a = Plasma concentration increased 25% in some patients, generally those on a twice
a day dosing regimen of phenytoin.
b = Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated
Phenytoin
NC or 25% increasea
48% decrease
Carbamazepine (CBZ)
NC
40% decrease
CBZ epoxideb
NC
NE
Valproic acid
11% decrease
14% decrease
Phenobarbital
NC 
NE
Primidone
NC
NE
Lamotrigine
NC at TPM doses up to 400 mg/day
13% decrease



Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
↓ = Decreased (induces lamotrigine glucuronidation).
↑ = Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
Concomitant Drug 
Effect on Concentration of 
Lamotrigine or Concomitant Drug 
Clinical Comment 
Estrogen-containing oral 
contraceptive 
preparations containing 30 mcg 
ethinylestradiol and 150 mcg levonorgestrel 
↓ lamotrigine 

↓ levonorgestrel 
Decreased lamotrigine concentrations approximately 50%. 

Decrease in levonorgestrel component by 19%. 
Carbamazepine and carbamazepine epoxide 
↓ lamotrigine 


? carbamazepine epoxide 
Addition of carbamazepine decreases 
lamotrigine concentration approximately 40%. 
May increase carbamazepine epoxide levels. 
Lopinavir/ritonavir 
↓ lamotrigine 
Decreased lamotrigine concentration approximately 50%. 
Atazanavir/ritonavir 
↓ lamotrigine
Decreased lamotrigine AUC approximately 32%. 
Phenobarbital/Primidone 
↓ lamotrigine 
Decreased lamotrigine concentration
 approximately 40%. 
Phenytoin 
↓ lamotrigine 
Decreased lamotrigine concentration 
approximately 40%. 
Rifampin 
↓ lamotrigine 
Decreased lamotrigine AUC 
approximately 40%. 
Valproate 
↑ lamotrigine

 ? valproate 
Increased lamotrigine concentrations 
slightly more than 2-fold. 
There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.


Table name:
Table 8: Clinically Significant Drug Interactions with Clarithromycin
Drugs That Are Affected By Clarithromycin
Drug(s) with Pharmacokinetics Affected by Clarithromycin
Recommendation
Comments
Antiarrhythmics:
 
Disopyramide
Quinidine
Dofetilide
Amiodarone
Sotalol
Procainamide
 
 
 
 
 
 
 
 
 
 
 
 
Not Recommended
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disopyramide, Quinidine: There have been postmarketing reports of torsades de pointes occurring with concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QTc prolongation during coadministration of clarithromycin with these drugs [see Warnings and Precautions (5.3)].
 
Serum concentrations of these medications should also be monitored. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with disopyramide and quinidine.
 
There have been postmarketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide. Therefore, blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide.
Digoxin
Use With Caution
Digoxin: Digoxin is a substrate for P-glycoprotein (Pgp) and clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are co-administered, inhibition of Pgp by clarithromycin may lead to increased exposure of digoxin. Elevated digoxin serum concentrations in patients receiving clarithromycin and digoxin concomitantly have been reported in postmarketing surveillance. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Monitoring of serum digoxin concentrations should be considered, especially for patients with digoxin concentrations in the upper therapeutic range.
Oral Anticoagulants:
 
Warfarin
 
 
Use With Caution
 
 
Oral anticoagulants: Spontaneous reports in the postmarketing period suggest that concomitant administration of clarithromycin and oral anticoagulants may potentiate the effects of the oral anticoagulants. Prothrombin times should be carefully monitored while patients are receiving clarithromycin and oral anticoagulants simultaneously [see Warnings and Precautions (5.4)].
Antiepileptics:
 
Carbamazepine
 
 
Use With Caution
 
 
Carbamazepine: Concomitant administration of single doses of clarithromycin and carbamazepine has been shown to result in increased plasma concentrations of carbamazepine. Blood level monitoring of carbamazepine may be considered. Increased serum concentrations of carbamazepine were observed in clinical trials with clarithromycin. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with carbamazepine.
Antifungals:
 
Itraconazole
 
 
 
 
 
 
 
 
 
Use With Caution
 
 
 
 
 
 
 
 
 
 
Itraconazole: Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when administered concomitantly (see also Itraconazole under “Drugs That Affect Clarithromycin” in the table below). Clarithromycin may increase the plasma concentrations of itraconazole. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions.
Fluconazole
No Dose Adjustment
Fluconazole:  [see Pharmacokinetics (12.3)]
Anti-Gout Agents:
 
Colchicine (in patients with renal or hepatic impairment)
 
Colchicine (in patients with normal renal and hepatic function)
 
 
Contraindicated
 
 
 
Use With Caution
 
 
Colchicine: Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. The dose of colchicine should be reduced when co-administered with clarithromycin in patients with normal renal and hepatic function [see Contraindications (4.4) and Warnings and Precautions (5.4)].
Antipsychotics:
 
Pimozide
 
Quetiapine
 
 
Contraindicated
 
 
Pimozide:  [See Contraindications (4.2)]
Quetiapine: Quetiapine is a substrate for CYP3A4, which is inhibited by clarithromycin. Co-administration with clarithromycin could result in increased quetiapine exposure and possible quetiapine related toxicities. There have been postmarketing reports of somnolence, orthostatic hypotension, altered state of consciousness, neuroleptic malignant syndrome, and QT prolongation during concomitant administration. Refer to quetiapine prescribing information for recommendations on dose reduction if co-administered with CYP3A4 inhibitors such as clarithromycin.
Antispasmodics:
 
Tolterodine (patients deficient in CYP2D6 activity)
 
 
Use With Caution
 
 
Tolterodine: The primary route of metabolism for tolterodine is via. CYP2D6. However, in a subset of the population devoid of CYP2D6, the identified pathway of metabolism is via. CYP3A. In this population subset, inhibition of CYP3A results in significantly higher serum concentrations of tolterodine. Tolterodine 1 mg twice daily is recommended in patients deficient in CYP2D6 activity (poor metabolizers) when co-administered with clarithromycin.
Antivirals:
 
Atazanavir
 
 
 
 
 
Use With Caution
 
 
 
 
 
Atazanavir: Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction (see Atazanavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)].
Saquinavir (in patients with decreased renal function)
 
 
 
 
 
 
Saquinavir: Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A and there is evidence of a bi-directional drug interaction (see Saquinavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)].
Ritonavir
Etravirine
 
 
 
 
Ritonavir, Etravirine: (see Ritonavir and Etravirine under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)].
Maraviroc
 
 
 
 
 
 
 
 
 
Maraviroc: Clarithromycin may result in increases in maraviroc exposures by inhibition of CYP3A metabolism. See Selzentry® prescribing information for dose recommendation when given with strong CYP3A inhibitors such as clarithromycin.
 
Boceprevir (in patients with normal renal function)
Didanosine
 
No Dose Adjustment
 
Boceprevir: Both clarithromycin and boceprevir are  substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when co-administered. No dose adjustments are necessary for patients with normal renal function (see Victrelis® prescribing information).
Zidovudine
 
Zidovudine: Simultaneous oral administration of clarithromycin immediate-release tablets and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine concentrations. Administration of clarithromycin and zidovudine should be separated by at least two hours [see Pharmacokinetics (12.3)].
Calcium Channel Blockers:
 
Verapamil
 
 
 
 
Use With Caution
 
 
Verapamil: Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent verapamil, [see Warnings and Precautions (5.4)].
Amlodipine
Diltiazem
 
Amlodipine, Diltiazem: [See Warnings and Precautions (5.4)]
 
Nifedipine
 
 
Nifedipine: Nifedipine is a substrate for CYP3A. Clarithromycin and other macrolides are known to inhibit CYP3A. There is potential of CYP3A-mediated interaction between nifedipine and clarithromycin. Hypotension and peripheral edema were observed when clarithromycin was taken concomitantly with nifedipine [see Warnings and Precautions (5.4)].
Ergot Alkaloids:
 
Ergotamine
Dihydroergotamine
 
 
Contraindicated
 
 
Ergotamine, Dihydroergotamine: Postmarketing reports indicate that coadministration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system [see Contraindications (4.6)].
Gastroprokinetic  Agents:
 
Cisapride
 
 
Contraindicated
 
 
Cisapride: [See Contraindications (4.2)]
HMG-CoA Reductase Inhibitors:
 
Lovastatin
Simvastatin
 
 
 
Contraindicated
 
 
 
 
 
Lovastatin, Simvastatin, Atorvastatin, Pravastatin, Fluvastatin: [See Contraindications (4.5) and Warnings and Precautions (5.4)]
Atorvastatin
Pravastatin
Use With Caution
 
Fluvastatin
No Dose Adjustment
 
Hypoglycemic Agents:
 
Nateglinide
Pioglitazone
Repaglinide
Rosiglitazone
 
 
Use With Caution
 
 
Nateglinide, Pioglitazone, Repaglinide, Rosiglitazone: [See Warnings and Precautions (5.4) and Adverse Reactions (6.2)]
 
Insulin
 
Insulin: [See Warnings and Precautions (5.4) and Adverse Reactions (6.2)]
Immunosuppressants:
 
Cyclosporine
 
 
 
Use With Caution
 
 
Cyclosporine: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with cyclosporine.
Tacrolimus
 
Tacrolimus: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with tacrolimus.
Phosphodiesterase inhibitors:
 
Sildenafil
Tadalafil
Vardenafil
 
 
 
Use With Caution
 
 
 
Sildenafil, Tadalafil, Vardenafil: Each of these phosphodiesterase inhibitors is primarily metabolized by CYP3A, and CYP3A will be inhibited by concomitant administration of clarithromycin. Co-administration of clarithromycin with sildenafil, tadalafil, or vardenafil will result in increased exposure of these phosphodiesterase inhibitors. Co-administration of these phosphodiesterase inhibitors with clarithromycin is not recommended. Increased systemic exposure of these drugs may occur with clarithromycin; reduction of dosage for phosphodiesterase inhibitors should be considered (see their respective prescribing information).
Proton Pump Inhibitors:
 
Omeprazole
 
 
No Dose Adjustment
 
 
Omeprazole: The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when coadministered with clarithromycin as a result of increased omeprazole exposures [see Pharmacokinetics (12.3)] (see also Omeprazole under “Drugs That Affect Clarithromycin” in the table below).
Xanthine Derivatives:
 
Theophylline
 
 
Use With Caution
 
 
Theophylline: Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serum theophylline concentrations [see Pharmacokinetics (12.3)]. Monitoring of serum theophylline concentrations should be considered for patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range.
Triazolobenzodiazepines and Other Related Benzodiazepines:
 
Midazolam
 
 
 
 
 
 
 
Use With Caution
 
 
 
 
 
 
 
Midazolam: When oral midazolam is co-administered with clarithromycin, dose adjustments may be necessary and possible prolongation and intensity of effect should be anticipated [see Warnings and Precautions (5.4) and Pharmacokinetics (12.3)].
Alprazolam
Triazolam
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Triazolam, Alprazolam: Caution and appropriate dose adjustments should be considered when triazolam or alprazolam is co-administered with clarithromycin. There have been postmarketing reports of drug interactions and central nervous system (CNS) effects (e.g., somnolence and confusion) with the concomitant use of clarithromycin and triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested.
 
In postmarketing experience, erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines.
Temazepam
Nitrazepam
Lorazepam
No Dose Adjustment
Temazepam, Nitrazepam, Lorazepam: For benzodiazepines which are not metabolized by CYP3A (e.g., temazepam, nitrazepam, lorazepam), a clinically important interaction with clarithromycin is unlikely.
Cytochrome P450 Inducers:
 
Rifabutin
 
 
Use With Caution
 
 
Rifabutin: Concomitant administration of rifabutin and clarithromycin resulted in an increase in rifabutin, and decrease in clarithromycin serum levels together with an increased risk of uveitis (see Rifabutin under “Drugs That Affect Clarithromycin” in the table below).
Other Drugs
Metabolized by CYP3A:
 
Alfentanil
Bromocriptine
Cilostazol
Methylprednisole Vinblastine
Phenobarbital
St. John’s Wort
 
 
 
Use With Caution
 
 
 
There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with alfentanil, methylprednisolone, cilostazol, bromocriptine, vinblastine, phenobarbital, and St. John’s Wort.
Other Drugs Metabolized by CYP450 Isoforms Other than CYP3A:
 
 
Hexobarbital
Phenytoin
Valproate
Use With Caution
There have been postmarketing reports of interactions of clarithromycin with drugs not thought to be metabolized by CYP3A, including hexobarbital, phenytoin, and valproate.
Drugs that Affect Clarithromycin
Drug(s) that Affect the Pharmacokinetics of Clarithromycin
Recommendation
                                                                          Comments
Antifungals:
 
Itraconazole
 
 
Use With Caution
 
 
Itraconazole: Itraconazole may increase the plasma concentrations of clarithromycin. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions (see also Itraconazole under “Drugs That Are Affected By Clarithromycin” in the table above).
Antivirals:
 
Atazanavir
 
 
 
 
 
 
 
 
 
 
 
Use With Caution
 
 
 
 
 
 
 
 
 
 
 
 
Atazanavir: When clarithromycin is co-administered with atazanavir, the dose of clarithromycin should be decreased by 50% [see Clinical Pharmacology (12.3)].
 
Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with atazanavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium complex. Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.
Ritonavir (in patients with decreased renal function)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ritonavir: Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with ritonavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium [see Pharmacokinetics (12.3)].
 
Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.
Saquinavir (in patients with decreased renal function)
 
 
 
 
Saquinavir: When saquinavir is co-administered with ritonavir, consideration should be given to the potential effects of ritonavir on clarithromycin (refer to ritonavir above) [see Pharmacokinetics (12.3)].
Etravirine
 
 
 
 
 
 
 
 
 
 
 
 
 
Etravirine: Clarithromycin exposure was decreased by etravirine; however, concentrations of the active metabolite, 14-OH-clarithromycin, were increased. Because 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered; therefore alternatives to clarithromycin should be considered for the treatment of MAC.
Saquinavir (in patients with normal renal function) Ritonavir (in patients with normal renal function)
No Dose Adjustment
 
Proton Pump Inhibitors:
 
Omeprazole
 
 
Use With Caution
Omeprazole: Clarithromycin concentrations in the gastric tissue and mucus were also increased by concomitant administration of omeprazole [see Pharmacokinetics (12.3)].
Miscellaneous Cytochrome P450 Inducers:
 
Efavirenz
Nevirapine
Rifampicin
Rifabutin
Rifapentine
 
 
 
Use With Caution
 
 
 
Inducers of CYP3A enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine will increase the metabolism of clarithromycin, thus decreasing plasma concentrations of clarithromycin, while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. Alternative antibacterial treatment should be considered when treating patients receiving inducers of CYP3A. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with rifabutin (see Rifabutin under “Drugs That Are Affected By Clarithromycin” in the table above).


Table name:
AED Coadministered AED Concentration Topiramate Concentration
Phenytoin
NC or 25% increasePlasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
48% decrease


Carbamazepine (CBZ)
NC
40% decrease
CBZ epoxideIs not administered but is an active metabolite of carbamazepine.
NC
NE
Valproic acid
11% decrease
14% decrease
Phenobarbital
NC
NE
Primidone
NC
NE
Lamotrigine
NC at TPM doses up to 400 mg/day
13% decrease


Table name:
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Grapefruit juice Avoid grapefruit juice


Table name:
Specific Drugs Reported
also: other medications affecting blood elements which may modify hemostasis
dietary deficiencies
prolonged hot weather
unreliable PT/INR determinations
†Increased and decreased PT/INR responses have been reported.
acetaminophen
alcohol†
allopurinol
aminosalicylic acid
amiodarone HCl
argatroban
aspirin
atenolol
atorvastatin†
azithromycin
bivalirudin
capecitabine
cefamandole
cefazolin
cefoperazone
cefotetan
cefoxitin
ceftriaxone
celecoxib
cerivastatin
chenodiol
chloramphenicol
chloral hydrate†
chlorpropamide
cholestyramine†
cimetidine
ciprofloxacin
cisapride
clarithromycin
clofibrate
cyclophosphamide†
danazol
dextran
dextrothyroxine
diazoxide
diclofenac
dicumarol
diflunisal
disulfiram
doxycycline
erythromycin
esomeprazole
ethacrynic acid
ezetimibe
fenofibrate
fenoprofen
fluconazole
fluorouracil
fluoxetine
flutamide
fluvastatin
fluvoxamine
gefitinib
gemifibrozil
glucagon
halothane
heparin
ibuprofen
ifosfamide
indomethacin
influenza virus vaccine
itraconazole
ketoprofen
ketorolac
lansoprazole
lepirudin
levamisole
levofloxacin
levothyroxine
liothyronine
lovastatin
mefenamic acid
methimazole†
methyldopa
methylphenidate
methylsalicylate
ointment (topical)
metronidazole
miconazole
(intravaginal, oral,
systemic)
moricizine
hydrochloride†
nalidixic acid
naproxen
neomycin
norfloxacin
ofloxacin
olsalazine
omeprazole
oxandrolone
oxaprozin
oxymetholone
pantoprazole
paroxetine
penicillin G,
intravenous
pentoxifylline
phenylbutazone
phenytoin†
piperacillin
piroxicam
pravastatin†
prednisone†
propafenone
propoxyphene
propranolol
propylthiouracil†
quinidine
quinine
rabeprazole
ranitidine†
rofecoxib
sertraline
simvastatin
stanozolol
streptokinase
sulfamethizole
sulfamethoxazole
sulfinpyrazone
sulfisoxazole
sulindac
tamoxifen
tetracycline
thyroid
ticarcillin
ticlopidine
tissue plasminogen
activator (t-PA)
tolbutamide
tramadol
trimethoprim/
sulfamethoxazole
urokinase
valdecoxib
valproate
vitamin E
warfarin overdose
zafirlukast
zileuton


Table name:
Table 8: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s) Recommendation Comments
Tizanidine Contraindicated Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)].
Theophylline Avoid Use (Plasma Exposure Likely to be Increased and Prolonged) Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions (5.6)] .
Drugs Known to Prolong QT Interval Avoid Use Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.10) and Use in Specific Populations (8.5)].
Oral antidiabetic drugs Use with caution Glucose-lowering effect potentiated Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were coadministered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported . Monitor blood glucose when ciprofloxacin is coadministered with oral antidiabetic drugs [see Adverse Reactions (6.1)] .
Phenytoin Use with caution Altered serum levels of phenytoin (increased and decreased) To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after coadministration of ciprofloxacin with phenytoin.
Cyclosporine Use with caution (transient elevations in serum creatinine) Monitor renal function (in particular serum creatinine) when ciprofloxacin is coadministered with cyclosporine.
Anti-coagulant drugs Use with caution (Increase in anticoagulant effect) The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after coadministration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole Use with caution Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after coadministration with ciprofloxacin [see Warnings and Precautions (5.15)].
Clozapine Use with caution Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after coadministration with ciprofloxacin are advised.
NSAIDs Use with caution Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil Use with caution 2-fold increase in exposure Monitor for sildenafil toxicity [see Pharmacokinetics (12.3)] .
Duloxetine Avoid Use 5-fold increase in duloxetine exposure If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx ®‡ (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products) Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2)]. Decrease ciprofloxacin absorption, resulting in lower serum and urine levels.
Probenecid Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels) Potentiation of ciprofloxacin toxicity may occur.


Table name:
AED  Co - administered
AED  Concentration
Topiramate 
Concentration

a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
b = Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated
Phenytoin
NC or 25% increase a
48% decrease
Carbamazepine (CBZ)
NC
40% decrease
CBZ epoxide b
NC
NE
Valproic acid
11% decrease
14% decrease
Phenobarbital
NC 
NE
Primidone
NC
NE
Lamotrigine
NC at TPM doses up to 400 mg/day
13% decrease



Table name:
Table 5: Clarithromycin Tissue Concentrations 2 hours after Dose1
1Mean ± (μg/g)
Tissue Clarithromycin Clarithromycin + Omeprazole
Antrum 10.48 ± 2.01 (n = 5) 19.96 ± 4.71 (n = 5)
Fundus 20.81 ± 7.64 (n = 5) 24.25 ± 6.37 (n = 5)
Mucus 4.15 ± 7.74 (n = 4) 39.29 ± 32.79 (n = 4)


Table name:
Table 8: Clinically Significant Drug Interactions with Clarithromycin
Drugs That Are Affected By Clarithromycin
Drug(s) with Pharmacokinetics Affected by Clarithromycin Recommendation Comments
Antiarrhythmics:


Disopyramide
Quinidine
Dofetilide
Amiodarone
Sotalol
Procainamide
Not Recommended Disopyramide, Quinidine: There have been postmarketing reports of torsades de pointes occurring with concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QTc prolongation during coadministration of clarithromycin with these drugs [see Warnings and Precautions (5.3)].

Serum concentrations of these medications should also be monitored. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with disopyramide and quinidine.

There have been postmarketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide. Therefore, blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide.


Digoxin Use With Caution Digoxin: Digoxin is a substrate for P-glycoprotein (Pgp) and clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are co-administered, inhibition of Pgp by clarithromycin may lead to increased exposure of digoxin. Elevated digoxin serum concentrations in patients receiving clarithromycin and digoxin concomitantly have been reported in postmarketing surveillance. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Monitoring of serum digoxin concentrations should be considered, especially for patients with digoxin concentrations in the upper therapeutic range.


Oral Anticoagulants:


Warfarin Use With Caution Oral anticoagulants: Spontaneous reports in the postmarketing period suggest that concomitant administration of clarithromycin and oral anticoagulants may potentiate the effects of the oral anticoagulants. Prothrombin times should be carefully monitored while patients are receiving clarithromycin and oral anticoagulants simultaneously [see Warnings and Precautions (5.4)].


Antiepileptics:


Carbamazepine Use With Caution Carbamazepine: Concomitant administration of single doses of clarithromycin and carbamazepine has been shown to result in increased plasma concentrations of carbamazepine. Blood level monitoring of carbamazepine may be considered. Increased serum concentrations of carbamazepine were observed in clinical trials with clarithromycin. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with carbamazepine.


Antifungals:


Itraconazole Use With Caution Itraconazole: Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when administered concomitantly (see also Itraconazole under “Drugs That Affect Clarithromycin” in the table below). Clarithromycin may increase the plasma concentrations of itraconazole. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions.


Fluconazole No Dose Adjustment


Fluconazole: [see Pharmacokinetics (12.3)]
Anti-Gout Agents:


Colchicine (in patients with renal or hepatic impairment)


Colchicine (in patients with normal renal and hepatic function)
Contraindicated




Use With Caution
Colchicine: Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. The dose of colchicine should be reduced when co-administered with clarithromycin in patients with normal renal and hepatic function [see Contraindications (4.4) and Warnings and Precautions (5.4)].


Antipsychotics:


Pimozide Contraindicated Pimozide: [See Contraindications (4.2)]


Quetiapine Quetiapine: Quetiapine is a substrate for CYP3A4, which is inhibited by clarithromycin. Co-administration with clarithromycin could result in increased quetiapine exposure and possible quetiapine related toxicities. There have been postmarketing reports of somnolence, orthostatic hypotension, altered state of consciousness, neuroleptic malignant syndrome, and QT prolongation during concomitant administration. Refer to quetiapine prescribing information for recommendations on dose reduction if co-administered with CYP3A4 inhibitors such as clarithromycin.


Antispasmodics:


Tolterodine (patients deficient in CYP2D6 activity) Use With Caution Tolterodine: The primary route of metabolism for tolterodine is via CYP2D6. However, in a subset of the population devoid of CYP2D6, the identified pathway of metabolism is via CYP3A. In this population subset, inhibition of CYP3A results in significantly higher serum concentrations of tolterodine. Tolterodine 1 mg twice daily is recommended in patients deficient in CYP2D6 activity (poor metabolizers) when co-administered with clarithromycin.


Antivirals:


Atazanavir Use With Caution Atazanavir: Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction (see Atazanavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)].


Saquinavir (in patients with decreased renal function) Saquinavir: Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A and there is evidence of a bi-directional drug interaction (see Saquinavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)].


Ritonavir
Etravirine
Ritonavir, Etravirine: (see Ritonavir and Etravirine under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)].


Maraviroc Maraviroc: Clarithromycin may result in increases in maraviroc exposures by inhibition of CYP3A metabolism. See Selzentry® prescribing information for dose recommendation when given with strong CYP3A inhibitors such as clarithromycin.


Boceprevir (in patients with normal renal function)

Didanosine
No Dose Adjustment Boceprevir: Both clarithromycin and boceprevir are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when co-administered. No dose adjustments are necessary for patients with normal renal function (see Victrelis® prescribing information).


Zidovudine Zidovudine: Simultaneous oral administration of clarithromycin immediate-release tablets and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine concentrations. Administration of clarithromycin and zidovudine should be separated by at least two hours [see Pharmacokinetics (12.3)].

The impact of co-administration of clarithromycin extended-release tablets or granules and zidovudine has not been evaluated.


Calcium Channel Blockers:


Verapamil Use With Caution Verapamil: Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent verapamil, [see Warnings and Precautions (5.4)].


Amlodipine
Diltiazem


Amlodipine, Diltiazem: [See Warnings and Precautions (5.4)]
Nifedipine Nifedipine: Nifedipine is a substrate for CYP3A. Clarithromycin and other macrolides are known to inhibit CYP3A. There is potential of CYP3A-mediated interaction between nifedipine and clarithromycin. Hypotension and peripheral edema were observed when clarithromycin was taken concomitantly with nifedipine [see Warnings and Precautions (5.4)].


Ergot Alkaloids:


Ergotamine
Dihydroergotamine
Contraindicated Ergotamine, Dihydroergotamine: Postmarketing reports indicate that coadministration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system [see Contraindications (4.6)].


Gastroprokinetic Agents:


Cisapride Contraindicated Cisapride: [See Contraindications (4.2)]


HMG-CoA Reductase Inhibitors:


Lovastatin
Simvastatin
Contraindicated Lovastatin, Simvastatin, Atorvastatin, Pravastatin, Fluvastatin: [See Contraindications (4.5) and Warnings and Precautions (5.4)]

Atorvastatin
Pravastatin


Use With Caution
Fluvastatin

No Dose Adjustment


Hypoglycemic Agents:


Nateglinide
Pioglitazone
Repaglinide
Rosiglitazone


Use With Caution Nateglinide, Pioglitazone, Repaglinide, Rosiglitazone: [See Warnings and Precautions (5.4) and Adverse Reactions (6.2)]

Insulin Insulin: [See Warnings and Precautions (5.4) and Adverse Reactions (6.2)]


Immunosuppressants:


Cyclosporine Use With Caution Cyclosporine: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with cyclosporine.


Tacrolimus Tacrolimus: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with tacrolimus.


Phosphodiesterase inhibitors:


Sildenafil
Tadalafil
Vardenafil
Use With Caution Sildenafil, Tadalafil, Vardenafil: Each of these phosphodiesterase inhibitors is primarily metabolized by CYP3A, and CYP3A will be inhibited by concomitant administration of clarithromycin. Co-administration of clarithromycin with sildenafil, tadalafil, or vardenafil will result in increased exposure of these phosphodiesterase inhibitors. Co-administration of these phosphodiesterase inhibitors with clarithromycin is not recommended. Increased systemic exposure of these drugs may occur with clarithromycin; reduction of dosage for phosphodiesterase inhibitors should be considered (see their respective prescribing information).


Proton Pump Inhibitors:


Omeprazole No Dose Adjustment Omeprazole: The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when coadministered with clarithromycin as a result of increased omeprazole exposures [see Pharmacokinetics (12.3)] (see also Omeprazole under “Drugs That Affect Clarithromycin” in the table below).


Xanthine Derivatives:


Theophylline Use With Caution Theophylline: Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serum theophylline concentrations [see Pharmacokinetics (12.3)]. Monitoring of serum theophylline concentrations should be considered for patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range.


Triazolobenzodiazepines and Other Related Benzodiazepines:


Midazolam Use With Caution Midazolam: When oral midazolam is co-administered with clarithromycin, dose adjustments may be necessary and possible prolongation and intensity of effect should be anticipated [see Warnings and Precautions (5.4) and Pharmacokinetics (12.3)].


Alprazolam
Triazolam
Triazolam, Alprazolam: Caution and appropriate dose adjustments should be considered when triazolam or alprazolam is co-administered with clarithromycin. There have been postmarketing reports of drug interactions and central nervous system (CNS) effects (e.g., somnolence and confusion) with the concomitant use of clarithromycin and triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested.

In postmarketing experience, erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines.


Temazepam
Nitrazepam
Lorazepam
No Dose Adjustment Temazepam, Nitrazepam, Lorazepam: For benzodiazepines which are not metabolized by CYP3A (e.g., temazepam, nitrazepam, lorazepam), a clinically important interaction with clarithromycin is unlikely.


Cytochrome P450 Inducers:


Rifabutin Use With Caution Rifabutin: Concomitant administration of rifabutin and clarithromycin resulted in an increase in rifabutin, and decrease in clarithromycin serum levels together with an increased risk of uveitis (see Rifabutin under “Drugs That Affect Clarithromycin” in the table below).


Other Drugs Metabolized by CYP3A:


Alfentanil
Bromocriptine
Cilostazol
Methylprednisole
Vinblastine
Phenobarbital
St. John’s Wort


Use With Caution There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with alfentanil, methylprednisolone, cilostazol, bromocriptine, vinblastine, phenobarbital, and St. John’s Wort.
Other Drugs Metabolized by CYP450 Isoforms Other than CYP3A:


Hexobarbital
Phenytoin
Valproate
Use With Caution There have been postmarketing reports of interactions of clarithromycin with drugs not thought to be metabolized by CYP3A, including hexobarbital, phenytoin, and valproate.


Drugs that Affect Clarithromycin
Drug(s) that Affect the Pharmacokinetics of Clarithromycin Recommendation Comments
Antifungals:


Itraconazole

Use With Caution Itraconazole: Itraconazole may increase the plasma concentrations of clarithromycin. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions (see also Itraconazole under “Drugs That Are Affected By Clarithromycin” in the table above).


Antivirals:


Atazanavir Use With Caution Atazanavir: When clarithromycin is co-administered with atazanavir, the dose of clarithromycin should be decreased by 50% [see Clinical Pharmacology (12.3)].

Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with atazanavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium complex. Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.


Ritonavir (in patients with decreased renal function) Ritonavir: Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with ritonavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium [see Pharmacokinetics (12.3)].

Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.


Saquinavir (in patients with decreased renal function) Saquinavir: When saquinavir is co-administered with ritonavir, consideration should be given to the potential effects of ritonavir on clarithromycin (refer to ritonavir above) [see Pharmacokinetics (12.3)].


Etravirine Etravirine: Clarithromycin exposure was decreased by etravirine; however, concentrations of the active metabolite, 14-OH-clarithromycin, were increased. Because 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered; therefore alternatives to clarithromycin should be considered for the treatment of MAC.


Saquinavir (in patients with normal renal function) No Dose Adjustment
Ritonavir (in patients with normal renal function)


Proton Pump Inhibitors:


Omeprazole Use With Caution Omeprazole: Clarithromycin concentrations in the gastric tissue and mucus were also increased by concomitant administration of omeprazole [see Pharmacokinetics (12.3)].


Miscellaneous Cytochrome P450 Inducers:


Efavirenz
Nevirapine
Rifampicin
Rifabutin
Rifapentine
Use With Caution Inducers of CYP3A enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine will increase the metabolism of clarithromycin, thus decreasing plasma concentrations of clarithromycin, while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. Alternative antibacterial treatment should be considered when treating patients receiving inducers of CYP3A. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with rifabutin (see Rifabutin under “Drugs That Are Affected By Clarithromycin” in the table above).




Table name:
 Drugs that Affect Renal Function A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDS], COX-2 inhibitors may impair the excretion of digoxin.
 Antiarrthymics Dofetilide Concomitant administration with digoxin was associated with a higher rate of Torsades de pointes.
Sotalol Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
Dronedarone Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
 Parathyroid Hormone Analog Teriparatide Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
 Thyroid supplement Thyroid Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
 Sympathomimetics Epinephrine Norepinephrine Dopamine Can increase the risk of cardiac arrhythmias.
 Neuromuscular Blocking Agents Succinylcholine May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.
 Supplements Calcium If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
 Beta-adrenergic blockers and  calcium channel blockers Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.


Table name:
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
DRUG DESCRIPTION OF INTERACTION
Corticosteroids Decreases plasma salicylate level; tapering doses of steroids may promote salicylism.
Acidifying Agents Increases plasma salicylate level.
Alkalizing Agents Decreased plasma salicylate levels.


Table name:
I. Due to the competition of salicylate with other drugs for binding to serum albumin the following drug interactions may occur:
DRUG DESCRIPTION OF INTERACTION
Sulfonylureas Hypoglycemia potentiated.
Methotrexate Decreases tubular reabsorption; clinical toxicity from methotrexate can result.
Oral Anticoagulants Increased bleeding.
II. Drugs changing salicylate levels by altering renal tubular reabsorption:
DRUG DESCRIPTION OF INTERACTION
Corticosteroids Decreases plasma salicylate level; tapering doses of steroids may promote salicylism.
Acidifying Agents Increases plasma salicylate levels.
Alkanizing Agents Decreased plasma salicylate levels.
III. Drugs with complicated interactions with salicylates:
DRUG DESCRIPTION OF INTERACTION
Heparin Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients.
Pyrazinamide Inhibits pyrazinamide-induced hyperuricemia.
Uricosuric Agents Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited.
The following alterations of laboratory tests have been reported during salicylate therapy:
LABORATORY TESTS EFFECT OF SALICYLATES
Thyroid Function Decreased PBI; increased t3 uptake.
Urinary Sugar False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5g q.d.).
5-Hydroxyindole acetic acid False negative with fluorometric test.
Acetone ketone bodies False positive FeCI3 in Gerhardt reaction; red color persists with boiling.
17-OH corticosteroids False reduced values with >4.8g q.d. salicylate.
Vanilmandelic acid False reduced values.
Uric Acid May increase or decrease depending on dose.
Prothrombin Decreased levels; slightly increased prothrombin time.


Table name:

Figure 5: Mean Standing Systolic Blood Pressure Change from Baseline


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
↓= Decreased (induces lamotrigine glucuronidation).
↑= Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine Decreased lamotrigine concentrations approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? carbamazepine epoxide May increase carbamazepine epoxide levels.
Lopinavir/ritonavir ↓ lamotrigine Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir ↓ lamotrigine Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine Increased lamotrigine concentrations slightly more than 2-fold.
? valproate There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.


Table name:
Factors Dosage Adjustments for Aripiprazole
Known CYP2D6 Poor Metabolizers Administer half of usual dose
Known CYP2D6 Poor Metabolizersand strong CYP3A4 inhibitors Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors Administer half of usual dose
Strong CYP2D6 and CYP3A4inhibitors Administer a quarter of usual dose
Strong CYP3A4 inducers Double usual dose over 1 to 2 weeks


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
↓ = Decreased (induces lamotrigine glucuronidation).
↑ = Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
Concomitant Drug
Effect on Concentration
of Lamotrigine or
 Concomitant Drug
Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel
 ↓ lamotrigine
 
 ↓ levonorgestrel
Decreased lamotrigine concentrations approximately 50%.
 
Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide
 ↓ lamotrigine
 
 ? carbamazepine epoxide
Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
 
May increase carbamazepine epoxide levels.
Lopinavir/ritonavir
 ↓ lamotrigine
Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir
 ↓ lamotrigine
Decreased lamotrigine AUC approximately 32%
Phenobarbital/primidone
 ↓ lamotrigine
Decreased lamotrigine concentration approximately 40%.
Phenytoin
 ↓ lamotrigine
Decreased lamotrigine concentration approximately 40%.
Rifampin
 ↓ lamotrigine
Decreased lamotrigine AUC approximately 40%.
Valproate
 ↑ lamotrigine
 
 ? valproate
Increased lamotrigine concentrations slightly more than 2-fold.
 
There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.


Table name:
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., Itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin daily*
Grapefruit juice Avoid grapefruit juice


Table name:
AED  Co - administered
AED  Concentration
Topiramate 
Concentration

a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
b = Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated
Phenytoin
NC or 25% increase a
48% decrease
Carbamazepine (CBZ)
NC
40% decrease
CBZ epoxide b
NC
NE
Valproic acid
11% decrease
14% decrease
Phenobarbital
NC 
NE
Primidone
NC
NE
Lamotrigine
NC at TPM doses up to 400 mg/day
13% decrease



Table name:
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine ↓ levonorgestrel Decreased lamotrigine concentrations approximately 50% Decrease in levonorgestrel component by 19%
Carbamazepine and carbamazepine epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%
? carbamazepine epoxide May increase CBZ epoxide levels
Lopinavir/ritonavir ↓ lamotrigine Decreased lamotrigine concentration approximately 50%
Atazanavir/ritonavir ↓ lamotrigine Decreased lamotrigine AUC approximately 32%
Phenobarbital/Primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%
Phenytoin ↓ lamotrigine Decreased lamotrigine concentration approximately 40%
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%
Valproate ↑lamotrigine Increased lamotrigine concentrations slightly more than 2-fold
? valproate There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.


Table name:
Table 14: Clinically Important Drug Interactions: Effect of other Drugs on INTUNIV®
Concomitant Drug Name or Drug Class Clinical Rationale and Magnitude of Drug Interaction Clinical Recommendation
Strong and moderate CYP3A4 inhibitors, e.g., ketoconazole, fluconazole Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected resulting in an increase in exposure Consider dose reduction [see Dosage and administration (2.7)]
Strong and moderate CYP3A4 inducers, e.g., rifampin, efavirenz Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected resulting in a decrease in exposure Consider dose increase [see Dosage and administration (2.7)]


Table name:
Specific Drugs Reported
also: other medications affecting blood elements which may modify hemostasis
dietary deficiencies
prolonged hot weather
unreliable PT/INR determinations
†Increased and decreased PT/INR responses have been reported.
acetaminophen
alcohol†
allopurinol
aminosalicylic acid
amiodarone HCl
argatroban
aspirin
atenolol
atorvastatin†
azithromycin
bivalirudin
capecitabine
cefamandole
cefazolin
cefoperazone
cefotetan
cefoxitin
ceftriaxone
celecoxib
cerivastatin
chenodiol
chloramphenicol
chloral hydrate†
chlorpropamide
cholestyramine†
cimetidine
ciprofloxacin
cisapride
clarithromycin
clofibrate
cyclophosphamide†
danazol
dextran
dextrothyroxine
diazoxide
diclofenac
dicumarol
diflunisal
disulfiram
doxycycline
erythromycin
esomeprazole
ethacrynic acid
ezetimibe
fenofibrate
fenoprofen
fluconazole
fluorouracil
fluoxetine
flutamide
fluvastatin
fluvoxamine
gefitinib
gemifibrozil
glucagon
halothane
heparin
ibuprofen
ifosfamide
indomethacin
influenza virus vaccine
itraconazole
ketoprofen
ketorolac
lansoprazole
lepirudin
levamisole
levofloxacin
levothyroxine
liothyronine
lovastatin
mefenamic acid
methimazole†
methyldopa
methylphenidate
methylsalicylate
ointment (topical)
metronidazole
miconazole
(intravaginal, oral,
systemic)
moricizine
hydrochloride†
nalidixic acid
naproxen
neomycin
norfloxacin
ofloxacin
olsalazine
omeprazole
oxandrolone
oxaprozin
oxymetholone
pantoprazole
paroxetine
penicillin G,
intravenous
pentoxifylline
phenylbutazone
phenytoin†
piperacillin
piroxicam
pravastatin†
prednisone†
propafenone
propoxyphene
propranolol
propylthiouracil†
quinidine
quinine
rabeprazole
ranitidine†
rofecoxib
sertraline
simvastatin
stanozolol
streptokinase
sulfamethizole
sulfamethoxazole
sulfinpyrazone
sulfisoxazole
sulindac
tamoxifen
tetracycline
thyroid
ticarcillin
ticlopidine
tissue plasminogen
activator (t-PA)
tolbutamide
tramadol
trimethoprim/
sulfamethoxazole
urokinase
valdecoxib
valproate
vitamin E
warfarin overdose
zafirlukast
zileuton


Table name:
AED Coadministered AED Concentration Topiramate Concentration
Phenytoin NC or 25% increase= Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. 48% decrease
Carbamazepine (CBZ) NC 40% decrease
CBZ epoxide= Is not administered but is an active metabolite of carbamazepine. NC NE
Valproic acid 11% decrease 14% decrease
Phenobarbital NC NE
Primidone NC NE
Lamotrigine NC at TPM doses up to 400 mg/day 13% decrease


Table name:
Drug Effect
Phenylephrine with prior administration of monoamine oxidase inhibitors (MAOI). Cardiac pressor response potentiated. May cause acute hypertensive crisis.
Phenylephrine with tricyclic antidepressants. Pressor response increased.
Phenylephrine with ergot alkaloids. Excessive rise in blood pressure.
Phenylephrine with bronchodilator sympathomimetic agents and with epinephrine or other sympathomimetics. Tachycardia or other arrhythmias may occur.
Phenylephrine with prior administration of propranolol or other β-adrenergic blockers. Cardiostimulating effects blocked.
Phenylephrine with atropine sulfate. Reflex bradycardia blocked; pressor response enhanced.
Phenylephrine with prior administration of phentolamine or other α-adrenergic blockers. Pressor response decreased.
Phenylephrine with diet preparations, such as amphetamines or phenylpropanolamine. Synergistic adrenergic response.


Table name:
 Interacting Drug 
 Interaction 
 Multivalent cation-containing products including antacids, metal cations or didanosine 
 Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
 Warfarin 
 Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
 Antidiabetic agents 
 Carefully monitor blood glucose (5.11, 7.3)


Table name:
Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
 * Change relative to reference
 Coadministered Drug
 Dosing Schedule
 Effect on Active
Moiety (Risperidone + 9-
Hydroxy- Risperidone (Ratio*)
 Risperidone Dose
Recommendation
 
 Coadministered Drug
 Risperidone
 AUC
 Cmax
 
 Enzyme (CYP2D6)
Inhibitors
 
 
 
 
 
 Fluoxetine
 20 mg/day 
 2 or 3 mg twice
daily
 1.4 
 1.5
 Re-evaluate dosing. Do not exceed 8 mg/day
 Paroxetine
 10 mg/day 
 4 mg/day
 1.3
 -
 Re-evaluate dosing. 
 
 20 mg/day 
 4 mg/day
 1.6
 -
 Do not exceed 8 mg/day
 
 40 mg/day 
 4 mg/day
 1.8
 -
 
 Enzyme (CYP3A/ PgP inducers) Inducers
 
 
 
 
 
 Carbamazepine 
 573 ± 168 mg/day
 3 mg twice daily
 0.51 
 0.55
 Titrate dose upwards.
Do not exceed twice the patient’s usual dose
 Enzyme (CYP3A)
Inhibitors
 
 
 
 
 
 Ranitidine 
 150 mg twice daily
 1 mg single dose
 1.2 
 1.4
 Dose adjustment not
needed
 Cimetidine 
 400 mg twice daily
 1 mg single dose
 1.1 
 1.3
 Dose adjustment not
needed
 Erythromycin 

 500 mg four times
daily
 1 mg single dose
 1.1 
 0.94
 Dose adjustment not
needed
 
 
 
 
 
 
 Other Drugs
 
 
 
 
 
 Amitriptyline 
 50 mg twice daily
 3 mg twice daily
 1.2 
 1.1
 Dose adjustment not
needed


Table name: FactorsDosage Adjustments for AripiprazoleAdminister half of usual doseAdminister a quarter of usual doseStrong CYP2D6 or CYP3A4 inhibitorsAdminister half of usual doseStrong CYP2D6 and CYP3A4 inhibitorsAdminister a quarter of usual doseStrong CYP3A4 inducersDouble usual dose over 1 to 2 weeks
 
 
Known CYP2D6 Poor Metabolizers
 
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors
 
 
 
 
 
 
 


Table name:
Table 10 Drugs That Should Not Be Coadministered With VIRACEPT
Drug Class: Drug Name Clinical Comment
Alpha 1-adrenoreceptor antagonist:
alfuzosin
Potentially increased alfuzosin concentrations can result in hypotension.
Antiarrhythmics:
amiodarone, quinidine
CONTRAINDICATED due to potential for serious and/or life threatening reactions such as cardiac arrhythmias.
Antimycobacterial:
rifampin
May lead to loss of virologic response and possible resistance to VIRACEPT or other coadministered antiretroviral agents.
Ergot Derivatives:
dihydroergotamine, ergonovine, ergotamine, methylergonovine
CONTRAINDICATED due to potential for serious and/or life threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
Herbal Products:
St. John's wort (hypericum perforatum)
May lead to loss of virologic response and possible resistance to VIRACEPT or other coadministered antiretroviral agents.
HMG-CoA Reductase Inhibitors:
lovastatin, simvastatin
Potential for serious reactions such as risk of myopathy including rhabdomyolysis.
Neuroleptic:
pimozide
CONTRAINDICATED due to potential for serious and/or life threatening reactions such as cardiac arrhythmias.
PDE5 inhibitor:
sildenafil (REVATIO) [for treatment of pulmonary arterial hypertension]
A safe and effective dose has not been established when used with VIRACEPT. There is increased potential for sildenafil-associated adverse events (which include visual disturbances, hypotension, prolonged erection, and syncope).
Proton Pump Inhibitors Omeprazole decreases the plasma concentrations of nelfinavir. Concomitant use of proton pump inhibitors and VIRACEPT may lead to a loss of virologic response and development of resistance.
Sedative/Hypnotics:
midazolam, triazolam
CONTRAINDICATED due to potential for serious and/or life threatening reactions such as prolonged or increased sedation or respiratory depression.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Table 4. Mean (95% C.I.) maximal change in baseline in systolic blood pressure (mmHg) following vardenafil 10 and 20 mg in healthy volunteers on daily alpha-blocker therapy
Dosing of Vardenafil and Alpha-Blocker Separated by 6 Hours Simultaneous dosing of Vardenafil and Alpha-Blocker
Alpha-Blocker Vardenafil
10 mg
Placebo-Subtracted
Vardenafil
20 mg
Placebo-Subtracted
Vardenafil
10 mg
Placebo-Subtracted
Vardenafil
20 mg
Placebo-Subtracted
Terazosin
10 mg daily
Standing SBP -7 (-10, -3) -11 (-14, -7) -23 (-31, 16) Due to the sample size, confidence intervals may not be an accurate measure for these data. These values represent the range for the difference. -14 (-33, 11)
Supine SBP -5 (-8, -2) -7 (-11, -4) -7 (-25, 19) -7 (-31, 22)
Tamsulosin
0.4 mg daily
Standing SBP -4 (-8, -1) -8 (-11, -4) -8 (-14, -2) -8 (-14, -1)
Supine SBP -4 (-8, 0) -7 (-11, -3) -5 (-9, -2) -3 (-7, 0)


Table name:
NA = Not available/reported
Digoxin concentrations increased greater than 50%
   Digoxin Serum   
Concentration Increase
   Digoxin AUC Increase Recommendations
Amiodarone 70% NA Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring.
Captopril 58% 39%
Clarithromycin NA 70%
Dronedarone NA 150%
Gentamicin 129-212% NA
Erythromycin 100% NA
Itraconazole 80% NA
Lapatinib NA 180%
Propafenone NA 60-270%
Quinidine 100% NA
Ranolazine 50% NA
Ritonavir NA 86%
Telaprevir 50% 85%
Tetracycline 100% NA
Verapamil 50-75% NA
Digoxin concentrations increased less than 50%
Atorvastatin 22% 15% Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring.
Carvedilol 16% 14%
Conivaptan 33% 43%
Diltiazem 20% NA
Indomethacin 40% NA
Nefazodone 27% 15%
Nifedipine 45% NA
Propantheline 24% 24%
Quinine NA 33%
Rabeprazole 29% 19%
Saquinavir 27% 49%
Spironolactone      25% NA
Telmisartan 20-49% NA
Ticagrelor 31% 28%
Tolvaptan 30% 20%
Trimethoprim 22-28% NA
Digoxin concentrations increased, but magnitude is unclear
Alprazolam, azithromycin, cyclosporine, diclofenac, diphenoxylate, epoprostenol, esomeprazole, ibuprofen, ketoconazole, lansoprazole, metformin, omeprazole Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin concentrations decreased
Acarbose, activated charcoal, albuterol, antacids, certain cancer chemotherapy or radiation therapy, cholestyramine, colestipol, extenatide, kaolin-pectin, meals high in bran, metoclopramide, miglitol, neomycin, penicillamine, phenytoin, rifampin, St. John’s Wort, sucralfate and sulfasalazine Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20-40% as necessary.


Table name:
Factors Dosage Adjustments for ABILIFY
Known CYP2D6 Poor Metabolizers Administer half of usual dose
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors Administer half of usual dose
Strong CYP2D6 and CYP3A4 inhibitors Administer a quarter of usual dose
Strong CYP3A4 inducers Double usual dose over 1 to 2 weeks


Table name:
Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme
Inhibitors
Inducers
CYP2C9 
amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast
aprepitant, bosentan, carbamazepine, phenobarbital, rifampin 
CYP1A2 
acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton
montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking 
CYP3A4 
alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton
armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide 


Table name:
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Digoxin concentrations increased greater than 50%
Digoxin Serum Concentration Increase Digoxin AUC Increase Recommendations
Amiodarone 70% NA Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30% to 50% or by modifying the dosing frequency and continue monitoring.
Captopril 58% 39%
Clarithromycin NA 70%
Dronedarone NA 150%
Gentamicin 129 to 212% NA
Erthromycin 100% NA
Itraconazole 60% NA
Lapatinib NA 180%
Propafenone NA 60 to 270 %
Quinidine 100% NA
Ranolazine 50% NA
Ritonavir NA 86%
Telaprevir 50% 85%
Tetracycline 100% NA
Verapamil 50 to 75% NA
Digoxin concentrations increased less than 50%
Atorvastatin 22% 15% Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15% to 30% or by modifying the dosing frequency and continue monitoring.
Carvedilol 16% 14%
Conivaptan 33% 43%
Diltiazem 20% NA
Indomethacin 40% NA
Nefazodone 27% 15%
Nifedipine 45% NA
Propantheline 24% 24%
Quinine NA 33%
Rabeprazole 29% 19%
Saquinavir 27% 49%
Spironolactone 25% NA
Telmisartan 20 to 49% NA
Ticagrelor 31% 28%
Tolvaptan 30% 20%
Trimethoprim 22 to28% NA
Digoxin concentrations increased, but magnitude is unclear
Alprazolam, azithromycin, cyclosporine, diclofenac, diphenoxylate, epoprostenol, esomeprazole, ibuprofen, ketoconazole, lansoprazole, metformin, omeprazole Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin concentrations decreased
Acarbose, activated charcoal, albuterol, antacids, certain cancer chemotherapy or radiation therapy, cholestyramine, colestipol, extenatide, kaolin-pectin, meals high in bran, metoclopramide, miglitol, neomycin, penicillamine, phenytoin, rifampin, St. John’s Wort, sucralfate, and sulfasalazine Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20 % to 40 % as necessary.


Table name:
  Interacting Agent   Examples
  Drugs whose efficacy is impaired by phenytoin
  Azoles   Fluconazole, ketoconazole, itraconazole, posaconazole, voriconazole
  Antineoplastic agents   Irinotecan, paclitaxel, teniposide
  Delavirdine   Phenytoin can substantially reduce the concentrations of delavirdine. This can lead to loss of virologic response and possible resistance [see Contraindications (4)].
  Neuromuscular blocking agents   Cisatracurium, pancuronium, rocuronium and vecuronium: resistance to the neuromuscular blocking action of the nondepolarizing neuromuscular blocking agents has occurred in patients chronically administered phenytoin. Whether or not phenytoin has the same effect on other non-depolarizing agents is unknown. Prevention or ManagementPatients should be monitored closely for more rapid recovery from neuromuscular blockade than expected, and infusion rate requirements may be higher.
  Warfarin   Increased and decreased PT/INR responses have been reported when phenytoin is coadministered with warfarin
  Other   Corticosteroids, doxycycline, estrogens, furosemide, oral contraceptives, paroxetine, quinidine, rifampin, sertraline, theophylline, and vitamin D
  Drugs whose level is decreased by phenytoin
  Antiepileptic drugsa   Carbamazepine, felbamate, lamotrigine, topiramate, oxcarbazepine
  Antilipidemic agents   Atorvastatin, fluvastatin, simvastatin
  Antiviral agents   Efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir Fosamprenavir: phenytoin when given with fosamprenavir alone may decrease the concentration of amprenavir, the active metabolite. Phenytoin when given with the combination of fosamprenavir and ritonavir may increase the concentration of amprenavir
Calcium channel blockers Nifedipine, nimodipine, nisoldipine, verapamil
Other Albendazole (decreases active metabolite), chlorpropamide, clozapine, cyclosporine, digoxin, folic acid, methadone, mexiletine, praziquantel, quetiapine


Table name:
  Bleeding times
  Clinical Impact:  Naproxen may decrease platelet aggregation and prolong bleeding time.
  Intervention:  This effect should be kept in mind when bleeding times are determined.
  Porter-Silber test
  Clinical Impact:  The administration of naproxen may result in increased urinary values for 17 ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
  Intervention:  Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
  Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
  Clinical Impact:  Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
  Intervention:  This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.


Table name:
I. Due to the competition of salicylate with other drugs for binding to serum albumin the following drug interactions may occur:
Drug Description of Interaction
Tolbutamide; Sulfonylureas Hypoglycemia potentiated
Methotrexate Decrease tubular reabsorption; clinical toxicity from methotrexate can result
Oral Anticoagulants Increased bleeding

II. Drugs changing salicylate levels by altering renal tubular reabsorption:
Drug Description of Interaction
Corticosteroids Decreases plasma salicylate level; tapering doses of steroids may promote salicylism
Ammonium Sulfate Increases plasma salicylate level

III. Drugs with complicated interactions with salicylates:
Drug Description of Interaction
Heparin Salicylate decreases platelet adhesivesness and interferes with hemostasis in heparin-treated patients
Pyrazinamide Inhibits pyrazinamide-induced hyperuricemia
Uricosuric Agents Effect of probenecid, sulfinpyrazone and phenylbutazone inhibited

The following alterations of laboratory tests have been reported during salicylate therapy6:
Laboratory Tests Effect of Salicylates
Thyroid Function Decreased PBI; increased T3 uptake
Urinary Sugar False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2 - 5 g qd)
5 Hydroxyindole Acetic Acid False negative with fluorometric test
Acetone, Ketone Bodies False positive FeCl3 in Gerhardt reaction; red color persists with boiling
17-OH Corticosteroids False reduced values with >4.8 g qd salicylate
Vanilmandelic Acid False reduced values
Uric Acid May increase or decrease depending on dose
Prothrombin Decreased levels; slightly increased prothrombin time


Table name:
Antiretrovirals 
Clinical Impact:  The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance [see C li n i cal P harmacology (12.3)] . Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see C l i n i cal  P harmacology (12.3)] . There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole. 
Intervention:  R il p i v i rine-containing products: Concomitant use with Omeprazole Delayed-Release Capsules is contraindicated [see C o ntraindications (4)]. A t azanavir: Avoid concomitant use with Omeprazole Delayed-Release Capsules. See prescribing information for atazanavir for dosing information. N elfinavir: Avoid concomitant use with Omeprazole Delayed-Release Capsules. See prescribing information for nelfinavir. S aquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities. Other antiretrovirals: See prescribing information for specific antiretroviral drugs. 
Warfarin 
Clinical Impact:  Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. 
Intervention:  Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range. 
Methotrexate 
Clinical Impact:  Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see W arnings and Precautions (5.11)]. 
Intervention:  A temporary withdrawal of Omeprazole Delayed-Release Capsules may be considered in some patients receiving high-dose methotrexate. 
CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam) 
Clopidogrel 
Clinical Impact:  Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see C li n i cal  P harmacology (12.3)] . There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel. 
Intervention:  Avoid concomitant use with Omeprazole Delayed-Release Capsules. Consider use of alternative anti-platelet therapy [see W arnings and Precautions (5.6)]. 
Citalopram 
Clinical Impact:  Increased exposure of citalopram leading to an increased risk of QT prolongation [ see   C li n i cal Pharmacology (12.3)]
Intervention:  Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing  information for citalopram. 
Cilostazol 
Clinical Impact:  Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see C l i nical Pharmacology (12.3)]. 
Intervention:  Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol. 
Phenytoin 
Clinical Impact:  Potential for increased exposure of phenytoin. 
Intervention:  Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin. 
Diazepam 
Clinical Impact:  Increased exposure of diazepam [see C l i nical Pharmacology (12.3)]
Intervention:   Monitor patients for increased sedation and reduce the dose of diazepam as needed. 
Digoxin 
Clinical Impact:  Potential for increased exposure of digoxin [see C l i n i c al Pharmacology (12.3)]. 
Intervention:  Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations.  See digoxin prescribing information. 
D rugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole) 
Clinical Impact:  Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity. 
Intervention:  Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving Omeprazole Delayed-Release Capsules and MMF. Use Omeprazole Delayed-Release Capsules with caution in transplant patients receiving MMF [see C l i nical  P harmacology (12.3)]. See the prescribing information for other drugs dependent on gastric pH for absorption. 
Combination Therapy with Clarithromycin and Amoxicillin 
Clinical Impact:  Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions. 
Intervention:  See Contraindications, Warnings and Precautions in prescribing information for clarithromycin. See Drug Interactions in prescribing information for amoxicillin. 
Tacrolimus 
Clinical Impact:  Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19. 
Intervention:  Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus. 
Interactions with Investigations of Neuroendocrine Tumors 
Clinical Impact:  Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see W arnings and Precautions (5.10) , C li n i cal   P harmacology (12.2)]
Intervention:  Temporarily stop Omeprazole Delayed-Release Capsules treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary. 
Interaction with Secretin Stimulation Test 
Clinical Impact:  Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma. 
Intervention:  Temporarily stop Omeprazole Delayed-Release Capsules treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see C li n i cal Pharmacology (12.2)]
False Positive Urine Tests for THC 
Clinical Impact:  There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs. 
Intervention:  An alternative confirmatory method should be considered to verify positive results. 
Other   
Clinical Impact:  There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram). 
Intervention:  Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with Omeprazole Delayed-Release Capsules. 


Table name:
Inhibitors of CYP3A4
Clinical Impact: The concomitant use of fentanyl transdermal system and CYP3A4 inhibitors can increase the plasma concentration of fentanyl, resulting in increased or prolonged opioid effects particularly when an inhibitor is added after a stable dose of fentanyl transdermal system is achieved [see Warnings and Precautions (5.5)].

After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the fentanyl transdermal system plasma concentration will decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to fentanyl.
Intervention: If concomitant use is necessary, consider dosage reduction of fentanyl transdermal system until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals.

If a CYP3A4 inhibitor is discontinued, consider increasing the fentanyl transdermal system dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
Examples Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir), grape fruit juice
CYP3A4 Inducers
Clinical Impact: The concomitant use of fentanyl transdermal system and CYP3A4 inducers can decrease the plasma concentration of fentanyl [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to fentanyl [see Warnings and Precautions (5.5)].

After stopping a CYP3A4 inducer, as the effects of the inducer decline, the fentanyl plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.
Intervention: If concomitant use is necessary, consider increasing the fentanyl transdermal system dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider fentanyl transdermal system dosage reduction and monitor for signs of respiratory depression.
Examples: Rifampin, carbamazepine, phenytoin
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.7)].
Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Warnings and Precautions 5.10].
Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue fentanyl transdermal system if serotonin syndrome is suspected.
Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome [see Warnings and Precautions (5.10)] or opioid toxicity (e.g., respiratory depression, coma).
Intervention: The use of fentanyl transdermal system is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples: phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact: May reduce the analgesic effect of fentanyl transdermal system and/or precipitate withdrawal symptoms.
Intervention: Avoid concomitant use.
Examples: butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact: Fentanyl transdermal system may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of fentanyl transdermal system and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when fentanyl transdermal system is used concomitantly with anticholinergic drugs.


Table name:
Table II. Clinically significant drug interactions with theophylline.Refer to PRECAUTIONS, Drug Interactions for further information regarding table.
Drug Type of Interaction Effect Average effect on steady-state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.
Adenosine Theophylline blocks adenosine receptors. Higher doses of adenosine may be required to achieve desired effect.
Alcohol A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours. 30% increase
Allopurinol Decreases theophylline clearance at allopurinol doses ≥600 mg/day. 25% increase
Aminoglutethimide Increases theophylline clearance by induction of microsomal enzyme activity. 25% decrease
Carbamazepine Similar to aminoglutethimide. 30% decrease
Cimetidine Decreases theophylline clearance by inhibiting cytochrome P450 1A2. 70% increase
Ciprofloxacin Similar to cimetidine. 40% increase
Clarithromycin Similar to erythromycin. 25% increase
Diazepam Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram Decreases theophylline clearance by inhibiting hydroxylation and demethylation. 50% increase
Enoxacin Similar to cimetidine. 300% increase
Ephedrine Synergistic CNS effects Increased frequency of nausea, nervousness, and insomnia.
Erythromycin Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3. 35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown. 30% increase
Flurazepam Similar to diazepam. Similar to diazepam.
Fluvoxamine Similar to cimetidine. Similar to cimetidine.
Halothane Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines. Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-A Decreases theophylline clearance. 100% increase
Isoproterenol (IV) Increase theophylline clearance. 20% increase
Ketamine Pharmacologic May lower theophylline seizure threshold.
Lithium Theophylline increases renal lithium clearance. Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam Similar to diazepam. Similar to diazepam.
Methotrexate (MTX) Decreases theophylline clearance. 20% increase after low dose MTX, higher dose MTX may have a greater effect.
Mexiletine Similar to disulfiram. 80% increase
Midazolam Similar to diazepam. Similar to diazepam.
Moricizine Increases theophylline clearance. 25% decrease
Pancuronium Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition. Larger dose of pancuronium may be required to achieve neuromuscular blockade.
Pentoxifylline Decreases theophylline clearance. 30% increase
Phenobarbital (PB) Similar to aminoglutethimide. 25% decrease after two weeks of concurrent PB.
Phenytoin Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption. Serum theophylline and phenytoin concentrations decrease about 40%.
Propafenone Decreases theophylline clearance and pharmacologic interaction. 40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Propranolol Similar to cimetidine and pharmacologic interaction. 100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Rifampin Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity. 20 to 40% decrease
Sulfinpyrazone Increase theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline. 20% increase
Tacrine Similar to cimetidine, also increases renal clearance of theophylline. 90% increase
Thiabendazole Decreases theophylline clearance. 190% increase
Ticlopidine Decreases theophylline clearance. 60% increase
Troleandomycin Similar to erythromycin. 33 to 100% increase depending on troleandomycin dose.
Verapamil Similar to disulfiram. 20% increase


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( , , , , , , ) 2.3 4 5.1 7.1 7.2 7.3 12.3
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Grapefruit juice Avoid grapefruit juice


Table name:
Drugs that Interfere with Hemostasis
Clinical Impact: Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:  Monitor patients with concomitant use of meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin  
Clinical Impact:   Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].
 Intervention: Concomitant use of meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. Meloxicam is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, or Beta-Blockers
Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).  In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: During concomitant use of meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam.
  Intervention: During concomitant use of meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [see Clinical Pharmacology (12.3)].
  Intervention: During concomitant use of meloxicam and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of meloxicam and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of meloxicam and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of meloxicam and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention: The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended.
Pemetrexed  
Clinical Impact: Concomitant use of meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended.


Table name:
Table 6: Predicted Drug Interactions with Didanosine Delayed-Release Capsules
Drug or Drug Class Effect Clinical Comment
Drugs that may cause pancreatic toxicity ↑risk of pancreatitis Use only with extreme caution.Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that cause pancreatic toxicity is required, suspension of didanosine delayed-release capsules is recommended [see Warnings and Precautions (5.1)].
Neurotoxic drugs ↑risk of neuropathy Use with caution.[See Warnings and Precautions (5.6)]. 
↑ Indicates increase. 


Table name:
Table 3: Drug Interactions: Pharmacokinetic Parameters for Coadministered Drug in the Presence of Indinavir (See PRECAUTIONS, Table 9 for Recommended Alterations in Dose or Regimen)
Coadministered drug Dose of Coadministered drug (mg) Dose of CRIXIVAN (mg) n Ratio (with/without CRIXIVAN) of Coadministered Drug
Pharmacokinetic Parameters
(90% CI); No Effect = 1.00
Cmax AUC Cmin
All interaction studies conducted in healthy, HIV-negative adult subjects, unless otherwise indicated.
Clarithromycin 500 twice daily,
7 days
800 three times daily, 7 days 12 1.19
(1.02, 1.39)
1.47
(1.30, 1.65)
1.97
(1.58, 2.46)
n=11
Efavirenz 200 once daily,
14 days
800 three times daily, 14 days 20 No significant change No significant change --
Ethinyl Estradiol
(ORTHO-NOVUM 1/35)Registered trademark of Ortho Pharmaceutical Corporation.
35 mcg, 8 days 800 three times daily, 8 days 18 1.02
(0.96, 1.09)
1.22
(1.15, 1.30)
1.37
(1.24, 1.51)
Isoniazid 300 once daily in the morning,
8 days
800 three times daily, 8 days 11 1.34
(1.12, 1.60)
1.12
(1.03, 1.22)
1.00
(0.92, 1.08)
MethadoneStudy conducted in subjects on methadone maintenance. 20-60 once daily in the morning,
8 days
800 three times daily, 8 days 12 0.93
(0.84, 1.03)
0.96
(0.86, 1.06)
1.06
(0.94, 1.19)
Norethindrone
(ORTHO-NOVUM 1/35)
1 mcg, 8 days 800 three times daily, 8 days 18 1.05
(0.95, 1.16)
1.26
(1.20, 1.31)
1.44
(1.32, 1.57)
Rifabutin
150 mg once daily in the morning, 11 days + indinavir compared to 300 mg once daily in the morning, 11 days alone
150 once daily in the morning,
10 days

300 once daily in the morning,
10 days
800 three times daily, 10 days


800 three times daily, 10 days
14



10
1.29
(1.05, 1.59)


2.34
(1.64, 3.35)
1.54
(1.33, 1.79)


2.73
(1.99, 3.77)
1.99
(1.71, 2.31)
n=13

3.44
(2.65, 4.46)
n=9
Ritonavir 100 twice daily,
14 days
800 twice daily,
14 days
10, 4Parallel group design; n for coadministered drug + indinavir, n for coadministered drug alone. 1.61
(1.13, 2.29)
1.72
(1.20, 2.48)
1.62
(0.93, 2.85)
200 twice daily,
14 days
800 twice daily,
14 days
9, 5 1.19
(0.85, 1.66)
1.96
(1.39, 2.76)
4.71
(2.66, 8.33)
n=9, 4
Saquinavir
   Hard gel formulation 600 single dose 800 three times daily, 2 days 6 4.7
(2.7, 8.1)
6.0
(4.0, 9.1)
2.9
(1.7, 4.7)C6hr
   Soft gel formulation 800 single dose 800 three times daily, 2 days 6 6.5
(4.7, 9.1)
7.2
(4.3, 11.9)
5.5
(2.2, 14.1)
   Soft gel formulation 1200 single dose 800 three times daily, 2 days 6 4.0
(2.7, 5.9)
4.6
(3.2, 6.7)
5.5
(3.7, 8.3)
Sildenafil 25 single dose 800 three times daily 6 See text below for discussion of interaction.
StavudineStudy conducted in HIV-positive subjects. 40 twice daily,
7 days
800 three times daily, 7 days 13 0.86
(0.73, 1.03)
1.21
(1.09, 1.33)
Not Done
Theophylline 250 single dose (on Days 1 and 7) 800 three times daily, 6 days (Days 2 to 7) 12, 4 0.88
(0.76, 1.03)
1.14
(1.04, 1.24)
1.13
(0.86, 1.49)
n=7, 3
Trimethoprim/
Sulfamethoxazole
   Trimethoprim 800 Trimethoprim/
160 Sulfamethoxazole q12h, 7 days
400 q6h, 7 days 12 1.18
(1.05, 1.32)
1.18
(1.05, 1.33)
1.18
(1.00, 1.39)
Trimethoprim/
Sulfamethoxazole
   Sulfamethoxazole 800 Trimethoprim/
160 Sulfamethoxazole q12h, 7 days
400 q6h, 7 days 12 1.01
(0.95, 1.08)
1.05
(1.01, 1.09)
1.05
(0.97, 1.14)
Vardenafil 10 single dose 800 three times daily 18 See text below for discussion of interaction.
Zidovudine 200 three times daily, 7 days 1000 three times daily, 7 days 12 0.89
(0.73, 1.09)
1.17
(1.07, 1.29)
1.51
(0.71, 3.20)
n=4
Zidovudine/
Lamivudine
   Zidovudine 200/150 three times daily, 7 days 800 three times daily, 7 days 6, 7 1.23
(0.74, 2.03)
1.39
(1.02, 1.89)
1.08
(0.77, 1.50)
n=5, 5
Zidovudine/
Lamivudine
   Lamivudine 200/150 three times daily, 7 days 800 three times daily, 7 days 6, 7 0.73
(0.52, 1.02)
0.91
(0.66, 1.26)
0.88
(0.59, 1.33)


Table name:
Interacting Agents
Prescribing Recommendation
Strong CYP3A4 inhibitors
(e.g,. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir nefazodone, cobicistat­containing products), gemfibrozil, cyclosporine, danazol
 
Contraindicated with simvastatin
 
Verapamil, diltiazem, dronedarone
Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine
Do not exceed 20 mg simvastatin daily
Lomitapide
For patients with HoFH, do not exceed 20 mg simvastatin daily*
Grapefruit juice
Avoid grapefruit juice


Table name:
Interacting Drug Interaction
Multivalent cation – containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.12, 7.3)


Table name:
AED Coadministered AED Concentration Topiramate Concentration
Phenytoin
NC or 25% increasePlasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
48% decrease


Carbamazepine (CBZ)
NC
40% decrease
CBZ epoxideIs not administered but is an active metabolite of carbamazepine.
NC
NE
Valproic acid
11% decrease
14% decrease
Phenobarbital
NC
NE
Primidone
NC
NE
Lamotrigine
NC at TPM doses up to 400 mg/day
13% decrease


Table name: Drugs That Interfere with HemostasisClinical Impact:• Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.Intervention:Monitor patients with concomitant use of VOLTAREN® GEL with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].AspirinClinical Impact:Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].Intervention:Concomitant use of VOLTAREN® GEL and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. VOLTAREN® GEL is not a substitute for low dose aspirin for cardiovascular protection.ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-BlockersClinical Impact:• NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.Intervention:• During concomitant use of VOLTAREN® GEL and ACE-inhibitors, ARBs, or beta- blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of VOLTAREN® GEL and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.DiureticsClinical Impact:Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.Intervention:During concomitant use of VOLTAREN® GEL with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].DigoxinClinical Impact:The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.Intervention:During concomitant use of VOLTAREN® GEL and digoxin, monitor serum digoxin levels.LithiumClinical Impact:NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.During concomitant use of VOLTAREN® GEL and lithium, monitor patients for signs of lithium toxicity.MethotrexateClinical Impact:Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).Intervention:During concomitant use of VOLTAREN® GEL and methotrexate, monitor patients for methotrexate toxicity.CyclosporineClinical Impact:Concomitant use of VOLTAREN® GEL and cyclosporine may increase cyclosporine's nephrotoxicity.Intervention:During concomitant use of VOLTAREN® GEL and cyclosporine, monitor patients for signs of worsening renal function.NSAIDs and SalicylatesClinical Impact:Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].Intervention:The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended.PemetrexedClinical Impact:Concomitant use of VOLTAREN® GEL and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).Intervention:During concomitant use of VOLTAREN® GEL and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and Gl toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
 
 
   
 
 
 
 
 
 
   
 
 
         
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
Intervention:
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
     


Table name:
Table 9: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction [See Clinical Pharmacology (12.3) for Magnitude of Interaction, Tables 12 and 13]
Concomitant Drug Class:
Drug Name
Effect on Concentration of Darunavir or Concomitant Drug Clinical Comment
HIV-1-Antiviral Agents: Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
didanosine ↔ darunavir
↔ didanosine
Didanosine should be administered one hour before or two hours after PREZISTA/ritonavir (which are administered with food).
HIV-1-Antiviral Agents: HIV-Protease Inhibitors (PIs)
indinavir
 
(The reference regimen for indinavir was indinavir/ritonavir 800/100 mg twice daily.)
↑ darunavir
↑ indinavir
The appropriate dose of indinavir in combination with PREZISTA/ritonavir has not been established.
lopinavir/ritonavir ↓ darunavir
↔ lopinavir
Appropriate doses of the combination have not been established. Hence, it is not recommended to co-administer lopinavir/ritonavir and PREZISTA, with or without ritonavir.
saquinavir ↓ darunavir
↔ saquinavir
Appropriate doses of the combination have not been established. Hence, it is not recommended to co-administer saquinavir and PREZISTA, with or without ritonavir.
HIV-1-Antiviral Agents: CCR5 co-receptor antagonists
maraviroc ↑ maraviroc Maraviroc concentrations are increased when co-administered with PREZISTA/ritonavir. When used in combination with PREZISTA/ritonavir, the dose of maraviroc should be 150 mg twice daily.
Other Agents
Antiarrhythmics:
bepridil,
lidocaine (systemic),
quinidine,
amiodarone,
flecainide,
propafenone
↑ antiarrhythmics Concentrations of these drugs may be increased when co-administered with PREZISTA/ritonavir. Caution is warranted and therapeutic concentration monitoring, if available, is recommended for antiarrhythmics when co-administered with PREZISTA/ritonavir.
digoxin ↑ digoxin The lowest dose of digoxin should initially be prescribed. The serum digoxin concentrations should be monitored and used for titration of digoxin dose to obtain the desired clinical effect.
Anticoagulant:
warfarin
↓ warfarin
↔ darunavir
Warfarin concentrations are decreased when co-administered with PREZISTA/ritonavir. It is recommended that the international normalized ratio (INR) be monitored when warfarin is combined with PREZISTA/ritonavir.
Anticonvulsant:
carbamazepine
↔ darunavir
↑ carbamazepine
The dose of either darunavir/ritonavir or carbamazepine does not need to be adjusted when initiating co-administration with darunavir/ritonavir and carbamazepine. Clinical monitoring of carbamazepine concentrations and its dose titration is recommended to achieve the desired clinical response.
Anticonvulsant:
phenobarbital,
phenytoin
↔ darunavir
↓ phenytoin
↓ phenobarbital
Co-administration of PREZISTA/ritonavir may cause a decrease in the steady-state concentrations of phenytoin and phenobarbital. Phenytoin and phenobarbital levels should be monitored when co-administering with PREZISTA/ritonavir.
Antidepressant:
trazodone,
desipramine
↑ trazodone
↑ desipramine
Concomitant use of trazodone or desipramine and PREZISTA/ritonavir may increase plasma concentrations of trazodone or desipramine which may lead to adverse events such as nausea, dizziness, hypotension and syncope. If trazodone or desipramine is used with PREZISTA/ritonavir, the combination should be used with caution, and a lower dose of trazodone or desipramine should be considered.
Anti-infective:
clarithromycin
↔ darunavir
↑ clarithromycin
No dose adjustment of the combination is required for patients with normal renal function. For patients with renal impairment, the following dose adjustments should be considered: For subjects with CLcr of 30–60 mL/min, the dose of clarithromycin should be reduced by 50%. For subjects with CLcr of < 30 mL/min, the dose of clarithromycin should be reduced by 75%.
Antifungals:
ketoconazole,
itraconazole,
voriconazole
↑ ketoconazole
↑ darunavir
↑ itraconazole
(not studied)
↓ voriconazole
(not studied)
Ketoconazole and itraconazole are potent inhibitors as well as substrates of CYP3A. Concomitant systemic use of ketoconazole, itraconazole, and darunavir/ritonavir may increase plasma concentration of darunavir.
Plasma concentrations of ketoconazole or itraconazole may be increased in the presence of darunavir/ritonavir. When co-administration is required, the daily dose of ketoconazole or itraconazole should not exceed 200 mg.
Plasma concentrations of voriconazole may be decreased in the presence of darunavir/ritonavir. Voriconazole should not be administered to patients receiving darunavir/ritonavir unless an assessment of the benefit/risk ratio justifies the use of voriconazole.
Anti-gout:
colchicine
↑ colchicine Treatment of gout-flares – co-administration of colchicine in patients on PREZISTA/ritonavir:
0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Treatment course to be repeated no earlier than 3 days.
 
Prophylaxis of gout-flares – co-administration of colchicine in patients on PREZISTA/ritonavir:
If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.
If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.

Treatment of familial Mediterranean fever – co-administration of colchicine in patients on PREZISTA/ritonavir:
maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Patients with renal or hepatic impairment should not be given colchicine with PREZISTA/ritonavir.
Antimycobacterial:
rifabutin
↑ darunavir
↑ rifabutin
↑ 25-O-desacetylrifabutin
Dose reduction of rifabutin by at least 75% of the usual dose (300 mg once daily) is recommended (i.e., a maximum dose of 150 mg every other day). Increased monitoring for adverse events is warranted in patients receiving this combination and further dose reduction of rifabutin may be necessary.
The reference regimen for rifabutin was 300 mg once daily
β-Blockers:
 
metoprolol,
timolol
↑ beta-blockers Caution is warranted and clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when co-administered with PREZISTA/ritonavir.
Benzodiazepines:
parenterally administered midazolam
↑ midazolam Concomitant use of parenteral midazolam with PREZISTA/ritonavir may increase plasma concentrations of midazolam. Co-administration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Co-administration of oral midazolam with PREZISTA/ritonavir is CONTRAINDICATED.
Calcium Channel
Blockers:
felodipine,
nifedipine,
nicardipine
↑ calcium channel blockers Plasma concentrations of calcium channel blockers (e.g., felodipine, nifedipine, nicardipine) may increase when PREZISTA/ritonavir are co-administered. Caution is warranted and clinical monitoring of patients is recommended.
Corticosteroid:
Systemic:
dexamethasone
↓ darunavir Systemic dexamethasone induces CYP3A and can thereby decrease darunavir plasma concentrations. This may result in loss of therapeutic effect to PREZISTA.
Corticosteroid:
Inhaled/Nasal:
fluticasone
↑ fluticasone Concomitant use of inhaled fluticasone and PREZISTA/ritonavir may increase plasma concentrations of fluticasone. Alternatives should be considered, particularly for long-term use.
Endothelin receptor antagonists:
bosentan
↑ bosentan Co-administration of bosentan in patients on PREZISTA/ritonavir:
In patients who have been receiving PREZISTA/ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

Co-administration of PREZISTA/ritonavir in patients on bosentan:
Discontinue use of bosentan at least 36 hours prior to initiation of PREZISTA/ritonavir. After at least 10 days following the initiation of PREZISTA/ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Hepatitis C Virus (HCV) Direct-Acting Agents:
NS3-4A protease inhibitors:

boceprevir
telaprevir
↓ darunavir
↓ boceprevir
↓ telaprevir
Concomitant administration of PREZISTA/ritonavir and boceprevir or telaprevir resulted in reduced steady-state exposures to darunavir and boceprevir or telaprevir. It is not recommended to co-administer boceprevir or telaprevir and PREZISTA/ritonavir.
HMG-CoA
Reductase Inhibitors:
pravastatin,
atorvastatin,
rosuvastatin
↑ pravastatin
↑ atorvastatin
↑ rosuvastatin
Titrate atorvastatin, pravastatin or rosuvastatin dose carefully and use the lowest necessary dose while monitoring for safety. Do not exceed atorvastatin 20 mg/day.
Immunosuppressants:
cyclosporine,
tacrolimus,
sirolimus
↑ immunosuppressants Plasma concentrations of cyclosporine, tacrolimus or sirolimus may be increased when co-administered with PREZISTA/ritonavir. Therapeutic concentration monitoring of the immunosuppressive agent is recommended when co-administered with PREZISTA/ritonavir.
Inhaled beta agonist:
salmeterol
↑ salmeterol Concurrent administration of salmeterol and PREZISTA/ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Narcotic Analgesic/Treatment of Opioid Dependence:
methadone,
buprenorphine,
buprenorphine/naloxone
↓ methadone
↔ buprenorphine, naloxone
↑ norbuprenorphine (metabolite)
No adjustment of methadone dosage is required when initiating co-administration of PREZISTA/ritonavir. However, clinical monitoring is recommended as the dose of methadone during maintenance therapy may need to be adjusted in some patients.
No dose adjustment for buprenorphine or buprenorphine/naloxone is required with concurrent administration of PREZISTA/ritonavir. Clinical monitoring is recommended if PREZISTA/ritonavir and buprenorphine or buprenorphine/naloxone are coadministered.
Neuroleptics:
risperidone,
thioridazine
↑ neuroleptics A dose decrease may be needed for these drugs when co-administered with PREZISTA/ritonavir.
Oral Contraceptives/estrogen:
ethinyl estradiol,
norethindrone
↓ ethinyl estradiol
↓ norethindrone
Plasma concentrations of ethinyl estradiol are decreased due to induction of its metabolism by ritonavir. Alternative methods of nonhormonal contraception are recommended.
PDE-5 inhibitors:
sildenafil,
vardenafil,
tadalafil
↑ PDE-5 inhibitors (only the use of sildenafil at doses used for treatment of erectile dysfunction has been studied with PREZISTA/ritonavir) Co-administration with PREZISTA/ritonavir may result in an increase in PDE-5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances and priapism.
Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH): Use of sildenafil is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) [see Contraindications (4) ]. The following dose adjustments are recommended for use of tadalafil with PREZISTA/ritonavir:
Co-administration of tadalafil in patients on PREZISTA/ritonavir:
In patients receiving PREZISTA/ritonavir for at least one week, start tadalafil at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.
Co-administration of PREZISTA/ritonavir in patients on tadalafil:
Avoid use of tadalafil during the initiation of PREZISTA/ritonavir. Stop tadalafil at least 24 hours prior to starting PREZISTA/ritonavir. After at least one week following the initiation of PREZISTA/ritonavir, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.
Use of PDE-5 inhibitors for erectile dysfunction:
Sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg dose in 72 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours can be used with increased monitoring for PDE-5 inhibitor-associated adverse events.
Selective Serotonin Reuptake Inhibitors (SSRIs):
sertraline,
paroxetine
↔ darunavir
↓ sertraline
↓ paroxetine
If sertraline or paroxetine is co-administered with PREZISTA/ritonavir, the recommended approach is a careful dose titration of the SSRI based on a clinical assessment of antidepressant response. In addition, patients on a stable dose of sertraline or paroxetine who start treatment with PREZISTA/ritonavir should be monitored for antidepressant response.


Table name:
Concomitant Drug Name or Drug Class
Clinical Rationale
Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine)
The concomitant use of aripiprazole tablets with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole tablets alone [seeCLINICALPHARMACOLOGY( 12.3)].
Withconcomitant use of aripiprazole tablets with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole tablets dosage [see DOSAGEANDADMINISTRATION (2.7)].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)
The concomitant use of aripiprazole tablets and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole tablets alone [see CLINICALPHARMACOLOGY (12.3)].
Withconcomitant use of aripiprazole tablets with a strong CYP3A4 inducer, consider increasing the aripiprazole tablets dosage [see DOSAGE ANDADMINISTRATION( 2.7)].
AntihypertensiveDrugs
Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.
Monitor bloodpressure and adjust dose accordingly [seeWARNINGS AND PRECAUTIONS (5.8)].
Benzodiazepines(e.g., lorazepam)
The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that
observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [seeWARNINGSANDPRECAUTIONS  (5.8)]
Monitor sedation and blood pressure. Adjust dose accordingly.


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T 4 and T 3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT 4. Continued administration results in a decrease in serum T 4 and normal FT 4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T 4 and T 3 to TBG and transthyretin. An initial increase in serum FT 4, is followed by return of FT 4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T 4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T 4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T 4 to T 3, leading to decreased T 3 levels. However, serum T 4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T 3 and T 4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T 3 concentrations by 30% with minimal change in serum T 4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T 3 and T 4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 18: Summary of Effect of Co-administered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Co-administered Drug Dosing Schedule Effect on Active Moiety (Risperidone + 9-Hydroxy- Risperidone(RatioChange relative to reference) Risperidone Dose Recommendation
Co-administered Drug Risperidone AUC Cmax
Enzyme (CYP2D6) Inhibitors
Fluoxetine 20 mg/day 2 or 3 mg
twice daily
1.4 1.5 Re-evaluate dosing.
Do not exceed 8 mg/day
Paroxetine 10 mg/day 4 mg/day 1.3 - Re-evaluate dosing.
Do not exceed 8 mg/day
20 mg/day 4 mg/day 1.6 -
40 mg/day 4 mg/day 1.8 -
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine 573 ± 168 mg/day 3 mg
twice daily
0.51 0.55 Titrate dose upwards.
Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine 150 mg twice daily 1 mg single dose 1.2 1.4 Dose adjustment not needed
Cimetidine 400 mg twice daily 1 mg single dose 1.1 1.3 Dose adjustment not needed
Erythromycin 500 mg
four times daily
1 mg single dose 1.1 0.94 Dose adjustment not needed
Other Drugs
Amitriptyline 50 mg twice daily 3 mg twice daily 1.2 1.1 Dose adjustment not needed


Table name:
Table 3: Drugs that Can Increase the Risk of Bleeding
 Drug Class  Specific Drugs
 Anticoagulants  argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
 Antiplatelet Agents  aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
 Nonsteroidal Anti-Inflammatory Agents  celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
 Serotonin Reuptake Inhibitors  citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
Oral hypoglycemics
Coumarin-type anticoagulants
Phenytoin
Cyclosporine
Rifampin
Theophylline
Voriconazole
Tofacitinib
Oral Contraceptives
Hydrochlorothiazide
Amitriptyline, nortriptyline
Azithromycin
Calcium Channel Blockers
Cyclophosphamide
Quinidine
Halofantrine
Losartan
Non-steroidal anti-inflammatory drugs
Saquinavir
Vinca Alkaloids
Zidovudine
Terfenadine
Cisapride
Astemizole
Rifabutin
Tacrolimus
Short-acting benzodiazepines
Triazolam
Pimozide
Alfentanil
Amphotericin B
Carbamazepine
Celecoxib
Fentanyl
HMG-CoA reductase inhibitors
Methadone
Prednisone
Sirolimus
Vitamin A


Table name:
AED  Coadministered
AED  Concentration
Topiramate 
Concentration

a = Plasma concentration increased 25% in some patients, generally those on a twice
a day dosing regimen of phenytoin.
b = Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated
Phenytoin
NC or 25% increasea
48% decrease
Carbamazepine (CBZ)
NC
40% decrease
CBZ epoxideb
NC
NE
Valproic acid
11% decrease
14% decrease
Phenobarbital
NC 
NE
Primidone
NC
NE
Lamotrigine
NC at TPM doses up to 400 mg/day
13% decrease



Table name:
Drug/Drug Class (Mechanism of Interaction by Voriconazole) Drug Plasma Exposure
(Cmax and AUCτ)
Recommendations for Drug Dosage Adjustment/Comments
Sirolimus*
(CYP3A4 Inhibition)
Significantly Increased Contraindicated
Rifabutin*
(CYP3A4 Inhibition)
Significantly Increased Contraindicated
Efavirenz (400 mg q 24h)**
(CYP3A4 Inhibition)
Efavirenz (300 mg q 24h) ** (CYP3A4 Inhibition)
Significantly Increased Slight decrease in AUCt Contraindicated When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)**(CYP3A4 Inhibition) Low-dose Ritonavir (100 mg q12h)** No Significant Effect of Voriconazole on Ritonavir Cmax or AUCτ Slight Decrease in Ritonavir Cmax and AUCτ Contraindicated because of significant reduction of voriconazole Cmax and AUCτ
Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole Cmax and AUCτ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids
(CYP450 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Contraindicated
Cyclosporine*
(CYP3A4 Inhibition)
AUCτ Significantly Increased; No Significant Effect on Cmax When initiating therapy with voriconazole in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When voriconazole is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
Methadone***
(CYP3A4 Inhibition)
Increased Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl
(CYP3A4 Inhibition)
Increased Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see DRUG INTERACTIONS (7)]
Alfentanil
(CYP3A4 Inhibition)
Significantly Increased Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with voriconazole. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [see DRUG INTERACTIONS (7)].
Oxycodone
(CYP3A4 Inhibition)
Significantly Increased Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see DRUG INTERACTIONS (7)].
NSAIDs**** including ibuprofen and diclofenac (CYP2C9 Inhibition) Increased Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed. [see DRUG INTERACTIONS (7)].
Tacrolimus* (CYP3A4 Inhibition) Significantly Increased When initiating therapy with voriconazole in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazole is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin* (CYP2C9 Inhibition) Significantly Increased Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)** Increased Monitoring for adverse events related to oral contraceptives is recommended during coadministration.
Warfarin* (CYP2C9 Inhibition) Prothrombin Time Significantly Increased Monitor PT or other suitable anticoagulation tests. Adjustment of warfarin dosage may be needed.
Omeprazole* (CYP2C19/3A4 Inhibition) Significantly Increased When initiating therapy with voriconazole in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors (CYP3A4 Inhibition) In Vivo Studies Showed No Significant Effects on Indinavir Exposure No dosage adjustment for indinavir when coadministered with voriconazole tablets
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors
Other NNRTIs***** (CYP3A4 Inhibition) A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to NNRTI
Benzodiazepines (CYP3A4 Inhibition) In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.
HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition) In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition) In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition) Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed.
Everolimus (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Concomitant administration of voriconazole and everolimus is not recommended


Table name:
Inhibitors of CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6
Clinical Impact: Methadone undergoes hepatic N-demethylation by several cytochrome P450 (CYP) isoforms, including CYP3A4, CYP2B6, CYP2C19, CYP2C9, and CYP2D6. The concomitant use of methadone hydrochloride tablets and CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitors can increase the plasma concentration of methadone, resulting in increased or prolonged opioid effects, and may result in a fatal overdose, particularly when an inhibitor is added after a stable dose of methadone hydrochloride tablets is achieved. These effects may be more pronounced with concomitant use of drugs that inhibit more than one of the CYP enzymes listed above. After stopping a CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitor, as the effects of the inhibitor decline, the methadone plasma concentration can decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy or withdrawal symptoms in patients physically dependent on methadone.
Intervention: If concomitant use is necessary, consider dosage reduction of methadone hydrochloride tablets until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitor is discontinued, follow patients for signs of opioid withdrawal and consider increasing the methadone hydrochloride tablets dosage until stable drug effects are achieved.
Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir), fluconazole, fluvoxamine, some selective serotonin reuptake inhibitors (SSRIs) (e.g., sertraline, fluvoxamine)
Inducers of CYP3A4, CYP2B6, CYP2C19, or CYP2C9
Clinical Impact: The concomitant use of methadone hydrochloride tablets and CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers can decrease the plasma concentration of methadone [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of withdrawal symptoms in patients physically dependent on methadone. These effects could be more pronounced with concomitant use of drugs that can induce multiple CYP enzymes. After stopping a CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducer, as the effects of the inducer decline, the methadone plasma concentration can increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression, sedation, or death.
Intervention: If concomitant use is necessary, consider increasing the methadone hydrochloride tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducer is discontinued, consider methadone hydrochloride tablets dosage reduction and monitor for signs of respiratory depression and sedation.
Examples: Rifampin, carbamazepine, phenytoin, St. John’s Wort, Phenobarbital
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death.
Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.6)].
Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Potentially Arrhythmogenic Agents
Clinical Impact: Pharmacodynamic interactions may occur with concomitant use of methadone and potentially arrhythmogenic agents or drugs capable of inducing electrolyte disturbances (hypomagnesemia, hypokalemia).
Intervention: Monitor patients closely for cardiac conduction changes.
Examples: Drugs known to have potential to prolong QT interval: Class I and III antiarrhythmics, some neuroleptics and tricyclic antidepressants, and calcium channel blockers. Drugs capable of inducing electrolyte disturbances: Diuretics, laxatives, and, in rare cases, mineralocortocoid hormones.
Serotonergic Drugs
Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Warnings and Precautions (5.8)].
Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue methadone hydrochloride tablets if serotonin syndrome is suspected.
Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome [see Warnings and Precautions (5.8)] or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)].
Intervention: The use of methadone hydrochloride tablets is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact: May reduce the analgesic effect of methadone hydrochloride tablets and/or precipitate withdrawal symptoms.
Intervention: Avoid concomitant use.
Examples: butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact: Methadone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of methadone hydrochloride tablets and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when methadone hydrochloride tablets are used concomitantly with anticholinergic drugs.


Table name:
Interacting  Agents 
Prescribing  Recommendations 
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, 
posaconazole, voriconazole, erythromycin, clarithromycin, 
telithromycin, HIV protease inhibitors, boceprevir, telaprevir, 
nefazodone, cobicistatcontaining products), gemfibrozil, 
cyclosporine, danazol 
 Contraindicated with simvastatin 
Verapamil, diltiazem, dronedarone
Do not exceed 10 mg simvastatin daily 
Amiodarone, amlodipine, ranolazine
Do not exceed 20 mg simvastatin daily 
Lomitapide
For patients with HoFH, do not exceed 
20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice 
Avoid grapefruit juice  


Table name:
Table 4 Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table 5 for Magnitude of Interaction.
* The interaction between immediate-release nevirapine tablets and the drug was evaluated in a clinical study. The results of drug interaction studies with immediate-release nevirapine tablets are expected to also apply to nevirapine extended-release tablets.
Drug Name
Effect on Concentration of Nevirapine or Concomitant Drug
Clinical Comment
HIV Antiviral Agents: Protease Inhibitors (PIs)
Atazanavir/Ritonavir*
↓ Atazanavir
↑ Nevirapine
Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures.
Fosamprenavir*
 
 
 
Fosamprenavir/Ritonavir*
↓ Amprenavir
↑ Nevirapine
 
 
↓ Amprenavir
↑ Nevirapine
 
Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.
 
No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied.
 
Indinavir*
↓ Indinavir
The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established.
Lopinavir/Ritonavir*
↓Lopinavir
Dosing in adult patients:
 
A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.
 
Dosing in pediatric patients:
 
Please refer to the Kaletra® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.
 
Nelfinavir*
↓ Nelfinavir M8 Metabolite 
↓ Nelfinavir Cmin
The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established.
Saquinavir/ritonavir
The interaction between nevirapine and saquinavir/ritonavir has not been evaluated
The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz*
↓ Efavirenz
The appropriate doses of these combinations with respect to safety and efficacy have not been established.
Delavirdine
Etravirine
Rilpivirine
 
Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial.
Hepatitis C Antiviral Agents
Boceprevir
Plasma concentrations of boceprevir may be decreased due to induction of CYP3A4/5 by nevirapine.
Nevirapine and boceprevir should not be coadministered because decreases in boceprevir plasma concentrations may result in a reduction in efficacy.
Telaprevir
Plasma concentrations of telaprevir may be decreased due to induction of CYP3A4 by nevirapine and plasma concentrations of nevirapine may be increased due to inhibition of CYP3A4 by telaprevir.
Nevirapine and telaprevir should not be coadministered because changes in plasma concentrations of nevirapine, telaprevir, or both may result in a reduction in telaprevir efficacy or an increase in nevirapine-associated adverse events.
Other Agents
Analgesics:
Methadone*
↓ Methadone
Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Antiarrhythmics:
Amiodarone, disopyramide, lidocaine
Plasma concentrations may be decreased.
Appropriate doses for this combination have not been established.
Antibiotics:
Clarithromycin*
↓ Clarithromycin
↑ 14-OH clarithromycin
Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.
Rifabutin*
↑ Rifabutin
Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.
Rifampin*
↓ Nevirapine
Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Anticonvulsants:
Carbamazepine, clonazepam, ethosuximide
Plasma concentrations of nevirapine and the anticonvulsant may be decreased.
Use with caution and monitor virologic response and levels of anticonvulsants.
Antifungals:
Fluconazole*
↑ Nevirapine
Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events.
Ketoconazole*
↓ Ketoconazole
Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.
Itraconazole
↓ Itraconazole
Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug.
Antithrombotics:
Warfarin
Plasma concentrations may be increased.
Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.
Calcium channel blockers:
Diltiazem, nifedipine, verapamil
Plasma concentrations may be decreased.
Appropriate doses for these combinations have not been established.
Cancer chemotherapy:
Cyclophosphamide
Plasma concentrations may be decreased.
Appropriate doses for this combination have not been established.
Ergot alkaloids:
Ergotamine
Plasma concentrations may be decreased.
Appropriate doses for this combination have not been established.
Immunosuppressants:
Cyclosporine, tacrolimus, sirolimus
Plasma concentrations may be decreased.
Appropriate doses for these combinations have not been established.
Motility agents:
Cisapride
Plasma concentrations may be decreased.
Appropriate doses for this combination have not been established.
Opiate agonists:
Fentanyl
Plasma concentrations may be decreased.
Appropriate doses for this combination have not been established.
Oral contraceptives:
Ethinyl estradiol and Norethindrone*
↓ Ethinyl estradiol
↓ Norethindrone
Despite lower ethinyl estradiol and norethindrone exposures when coadministered with nevirapine, literature reports suggest that nevirapine has no effect on pregnancy rates among HIV-infected women on combined oral contraceptives. When coadministered with nevirapine extended-release tablets, no dose adjustment of ethinyl estradiol or norethindrone is needed when used in combination for contraception

When oral contraceptives are used for hormonal regulation during nevirapine extended-release tablets therapy, the therapeutic effect of the hormonal therapy should be monitored. 


Table name:
Interacting Drug Interaction
Theophylline Serious and fatal reactions. Avoid concomitant use. Monitor serum level ( 7)
Warfarin Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding ( 7)
Antidiabetic agents Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose ( 7)
Phenytoin Monitor phenytoin level ( 7)
Methotrexate Monitor for methotrexate toxicity ( 7)
Cyclosporine May increase serum creatinine. Monitor serum creatinine ( 7)
Multivalent cation-containing products including antacids, metal cations or didanosine Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin ( 7)


Table name:
Interacting Agent Examples
Drugs whose efficacy is impaired by phenytoin
Azoles Fluconazole, ketoconazole, itraconazole, posaconazole, voriconazole
Antineoplastic agents Irinotecan, paclitaxel, teniposide
Delavirdine Phenytoin can substantially reduce the concentrations of delavirdine. This can lead to loss of virologic response and possible resistance [see Contraindications (4)].
Neuromuscular blocking agents Cisatracurium, pancuronium, rocuronium and vecuronium: resistance to the neuromuscular blocking action of the nondepolarizing neuromuscular blocking agents has occurred in patients chronically administered phenytoin. Whether or not phenytoin has the same effect on other non-depolarizing agents is unknown. Prevention or ManagementPatients should be monitored closely for more rapid recovery from neuromuscular blockade than expected, and infusion rate requirements may be higher.
Warfarin Increased and decreased PT/INR responses have been reported when phenytoin is coadministered with warfarin
Other Corticosteroids, doxycycline, estrogens, furosemide, oral contraceptives, paroxetine, quinidine, rifampin, sertraline, theophylline, and vitamin D
Drugs whose level is decreased by phenytoin
Antiepileptic drugsa Carbamazepine, felbamate, lamotrigine, topiramate, oxcarbazepine
Antilipidemic agents Atorvastatin, fluvastatin, simvastatin
Antiviral agents Efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir Fosamprenavir: phenytoin when given with fosamprenavir alone may decrease the concentration of amprenavir, the active metabolite. Phenytoin when given with the combination of fosamprenavir and ritonavir may increase the concentration of amprenavir
Calcium channel blockers Nifedipine, nimodipine, nisoldipine, verapamil
Other Albendazole (decreases active metabolite), chlorpropamide, clozapine, cyclosporine, digoxin, folic acid, methadone, mexiletine, praziquantel, quetiapine


Table name:
Table 3. Clinically Significant Drug Interactions with naproxen or sumatriptan
Ergot-Containing Drugs
Clinical Impact: Ergot-containing drugs have been reported to cause prolonged vasospastic reactions.
Intervention: Because these effects may be additive, coadministration of TREXIMET and ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) within 24 hours of each other is contraindicated.
Monoamine Oxidase-A Inhibitors
Clinical Impact: MAO-A inhibitors increase systemic exposure of orally administered sumatriptan by 7-fold.
Intervention: The use of TREXIMET in patients receiving MAO-A inhibitors is contraindicated.
Other 5-HT1 Agonists
Clinical Impact: 5-HT1 agonist drugs can cause vasospastic effects.
Intervention: Because these effects may be additive, coadministration of TREXIMET and other 5 HT1 agonists (e.g., triptans) within 24 hours of each other is contraindicated.
Drugs That Interfere with Hemostasis
Clinical Impact: Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of TREXIMET with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.16)].
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].
Intervention: Concomitant use of TREXIMET and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.16)].
Selective Serotonin Reuptake Inhibitors/Serotonin Norepinephrine Reuptake Inhibitors and Serotonin Syndrome
Clinical Impact: Cases of serotonin syndrome have been reported during coadministration of triptans and SSRIs, SNRIs, TCAs, and MAO inhibitors [see Warnings and Precautions (5.11)].
Intervention: Discontinue TREXIMET if serotonin syndrome is suspected.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-blockers
Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: During concomitant use of TREXIMET and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained [see Warnings and Precautions (5.8)]. During concomitant use of TREXIMET and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.8)].
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of TREXIMET with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.8, 5.12)].
Digoxin
Clinical Impact: The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of TREXIMET and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of TREXIMET and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant administration of some NSAIDs with high-dose methotrexate therapy has been reported to elevate and prolong serum methotrexate levels, resulting in deaths from severe hematologic and gastrointestinal toxicity. Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of TREXIMET and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of NSAIDs and cyclosporine may increase cyclosporine's nephrotoxicity.
Intervention: During concomitant use of TREXIMET and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention: The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of NSAIDs and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of TREXIMET and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.

In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Probenecid
Clinical Impact: Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly. The clinical significance of this is unknown.
Intervention: Reduce the frequency of administration of Treximet when given concurrently with probenecid.


Table name:
DRUG DISCRIPTION OF INTERACTION
Sulfonylureas Hypoglycemia potentiated
Methotrexate Decreases tubular reabsorption; clinical toxicity from methotrexate can result.
Oral Anticoagulants Increased bleeding


Table name:
Specific Drugs Reported
also: other medications affecting blood elements which may modify hemostasis dietary deficiencies prolonged hot weather unreliable PT/INR determinations †Increased and decreased PT/INR responses have been reported.



acetaminophen alcohol† allopurinol aminosalicylic acid amiodarone HCl argatroban aspirin atenolol atorvastatin† azithromycin bivalirudin capecitabine cefamandole cefazolin cefoperazone cefotetan cefoxitin ceftriaxone celecoxib cerivastatin chenodiol chloramphenicol chloral hydrate† chlorpropamide cholestyramine† cimetidine ciprofloxacin cisapride clarithromycin clofibrate cyclophosphamide† danazol dextran dextrothyroxine diazoxide

































diclofenac dicumarol diflunisal disulfiram doxycycline erythromycin esomeprazole ethacrynic acid ezetimibe fenofibrate fenoprofen fluconazole fluorouracil fluoxetine flutamide fluvastatin fluvoxamine gefitinib gemifibrozil glucagon halothane heparin ibuprofen ifosfamide indomethacin influenza virus vaccine itraconazole ketoprofen ketorolac lansoprazole lepirudin levamisole levofloxacin levothyroxine liothyronine

































lovastatin mefenamic acid methimazole† methyldopa methylphenidate methylsalicylate ointment (topical) metronidazole miconazole (intravaginal, oral, systemic) moricizine hydrochloride† nalidixic acid naproxen neomycin norfloxacin ofloxacin olsalazine omeprazole oxandrolone oxaprozin oxymetholone pantoprazole paroxetine penicillin G, intravenous pentoxifylline phenylbutazone phenytoin† piperacillin piroxicam pravastatin† prednisone† propafenone

































propoxyphene propranolol propylthiouracil† quinidine quinine rabeprazole ranitidine† rofecoxib sertraline simvastatin stanozolol streptokinase sulfamethizole sulfamethoxazole sulfinpyrazone sulfisoxazole sulindac tamoxifen tetracycline thyroid ticarcillin ticlopidine tissue plasminogen activator (t-PA) tolbutamide tramadol trimethoprim/ sulfamethoxazole urokinase valdecoxib valproate vitamin E warfarin overdose zafirlukast zileuton



































Table name:
Interacting Agents  Prescribing Recommendations 
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone  Avoid simvastatin 
Gemfibrozil, cyclosporine, danazol  Do not exceed 10 mg simvastatin daily 
Amiodarone, verapamil  Do not exceed 20 mg simvastatin daily 
Grapefruit juice  Avoid large quantities of grapefruit juice (>1 quart daily) 


Table name:
Table 2. Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T4 and T3 serum transport - but FT4 concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors
(SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 7: Selected Drug Interactions in Adults
Concomitant Drug Class:
Drug Name
Effect on Concentration of Raltegravir Clinical Comment
HIV-1-Antiviral Agents
atazanavir Atazanavir, a strong inhibitor of UGT1A1, increases plasma concentrations of raltegravir. However, since concomitant use of ISENTRESS with atazanavir/ritonavir did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended.
atazanavir/ritonavir Atazanavir/ritonavir increases plasma concentrations of raltegravir. However, since concomitant use of ISENTRESS with atazanavir/ritonavir did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended.
efavirenz Efavirenz reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.
etravirine Etravirine reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.
tipranavir/ritonavir Tipranavir/ritonavir reduces plasma concentrations of raltegravir. However, since comparable efficacy was observed for this combination relative to other ISENTRESS-containing regimens in Phase 3 studies 018 and 019, no dose adjustment is recommended.
Other Agents
omeprazole Coadministration of medicinal products that increase gastric pH (e.g., omeprazole) may increase raltegravir levels based on increased raltegravir solubility at higher pH. However, since concomitant use of ISENTRESS with proton pump inhibitors and H2 blockers did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended.
rifampin Rifampin, a strong inducer of UGT1A1, reduces plasma concentrations of raltegravir. The recommended dosage of ISENTRESS is 800 mg twice daily during coadministration with rifampin.


Table name:
Table 2. Clinically Significant Drug Interactions with Diclofenac
Drugs That Interfere with Hemostasis
Clinical Impact: Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of diclofenac sodium delayed-release tablets with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS: Hematologic Toxicity ).
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation ).
Intervention: Concomitant use of diclofenac sodium delayed-release tablets and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS: Hematologic Toxicity ). Diclofenac sodium delayed-release tablets are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: During concomitant use of diclofenac sodium delayed-release tablets and ACE-inhibitors, ARBs, or beta- blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of diclofenac sodium delayed-release tablets and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS: Renal Toxicity and Hyperkalemia ). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of diclofenac sodium delayed-release tablets with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS: Renal Toxicity and Hyperkalemia ).
Digoxin
Clinical Impact: The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of diclofenac sodium delayed-release tablets and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance . The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of diclofenac sodium delayed-release tablets and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of diclofenac sodium delayed-release tablets and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of diclofenac sodium delayed-release tablets and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of diclofenac sodium delayed-release tablets and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation ) .
Intervention: The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of diclofenac sodium delayed-release tablets and pemetrexed may increase the risk of pemetrexed‑ associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of diclofenac sodium delayed-release tablets and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
CYP2C9 Inhibitors or Inducers:
Clinical Impact: Diclofenac is metabolized by cytochrome P450 enzymes, predominantly by CYP2C9. Co-administration of diclofenac with CYP2C9 inhibitors (e.g. voriconazole) may enhance the exposure and toxicity of diclofenac whereas co‑administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of diclofenac.
Intervention: A dosage adjustment may be warranted when diclofenac is administered with CYP2C9 inhibitors or inducers (see CLINICAL PHARMACOLOGY: Pharmacokinetics ).


Table name:
Figure 2: Effect of venlafaxine on the pharmacokinetics interacting drugs and their active metabolites.


Table name: Tolterodine (patients deficient in CYP2D6 activity) Theophylline Use With Caution Midazolam Use With Caution Use With Caution
Table 8: Clinically Significant Drug Interactions with Clarithromycin
Drugs That Are Affected By Clarithromycin
Drug(s) with Pharmacokinetics Affected by Clarithromycin Recommendation Comments
Antiarrhythmics:


 
Disopyramide
Quinidine
Dofetilide
Amiodarone
Sotalol
Procainamide
Not Recommended Disopyramide, Quinidine: There have been postmarketing reports of torsades de pointes occurring with concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QTc prolongation during coadministration of clarithromycin with these drugs [see Warnings and Precautions (5.3)].

Serum concentrations of these medications should also be monitored. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with disopyramide and quinidine.

There have been postmarketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide. Therefore, blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide.


Digoxin Use With Caution Digoxin: Digoxin is a substrate for P-glycoprotein (Pgp) and clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are co-administered, inhibition of Pgp by clarithromycin may lead to increased exposure of digoxin. Elevated digoxin serum concentrations in patients receiving clarithromycin and digoxin concomitantly have been reported in postmarketing surveillance. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Monitoring of serum digoxin concentrations should be considered, especially for patients with digoxin concentrations in the upper therapeutic range.


Oral Anticoagulants:


   
Warfarin Use With Caution Oral anticoagulants: Spontaneous reports in the postmarketing period suggest that concomitant administration of clarithromycin and oral anticoagulants may potentiate the effects of the oral anticoagulants. Prothrombin times should be carefully monitored while patients are receiving clarithromycin and oral anticoagulants simultaneously [see Warnings and Precautions (5.4)].


Antiepileptics:


   
Carbamazepine Use With Caution Carbamazepine: Concomitant administration of single doses of clarithromycin and carbamazepine has been shown to result in increased plasma concentrations of carbamazepine. Blood level monitoring of carbamazepine may be considered. Increased serum concentrations of carbamazepine were observed in clinical trials with clarithromycin. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with carbamazepine.


Antifungals:


 
Itraconazole Use With Caution Itraconazole: Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when administered concomitantly (see also Itraconazole under “Drugs That Affect Clarithromycin” in the table below). Clarithromycin may increase the plasma concentrations of itraconazole. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions.


Fluconazole No Dose Adjustment


Fluconazole: [see Pharmacokinetics (12.3)]
Anti-Gout Agents:


 
Colchicine (in patients with renal or hepatic impairment)


Colchicine (in patients with normal renal and hepatic function)
Contraindicated




Use With Caution
Colchicine: Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. The dose of colchicine should be reduced when co-administered with clarithromycin in patients with normal renal and hepatic function [see Contraindications (4.4)and Warnings and Precautions (5.4)].


Antipsychotics:


 
Pimozide Contraindicated Pimozide: [See Contraindications (4.2)]


Quetiapine   Quetiapine: Quetiapine is a substrate for CYP3A4, which is inhibited by clarithromycin. Co-administration with clarithromycin could result in increased quetiapine exposure and possible quetiapine related toxicities. There have been postmarketing reports of somnolence, orthostatic hypotension, altered state of consciousness, neuroleptic malignant syndrome, and QT prolongation during concomitant administration. Refer to quetiapine prescribing information for recommendations on dose reduction if co-administered with CYP3A4 inhibitors such as clarithromycin.


Antispasmodics:


   
 
Use With Caution Tolterodine: The primary route of metabolism for tolterodine is via CYP2D6. However, in a subset of the population devoid of CYP2D6, the identified pathway of metabolism is via CYP3A. In this population subset, inhibition of CYP3A results in significantly higher serum concentrations of tolterodine. Tolterodine 1 mg twice daily is recommended in patients deficient in CYP2D6 activity (poor metabolizers) when co-administered with clarithromycin.


Antivirals:


   
Atazanavir Use With Caution Atazanavir: Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction (see Atazanavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)].


Saquinavir (in patients with decreased renal function)   Saquinavir: Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A and there is evidence of a bi-directional drug interaction (see Saquinavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)].


Ritonavir
Etravirine
  Ritonavir, Etravirine: (see Ritonavir and Etravirine under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)].


Maraviroc   Maraviroc: Clarithromycin may result in increases in maraviroc exposures by inhibition of CYP3A metabolism. See Selzentry® prescribing information for dose recommendation when given with strong CYP3A inhibitors such as clarithromycin.


Boceprevir (in patients with normal renal function)

Didanosine
No Dose Adjustment Boceprevir: Both clarithromycin and boceprevir are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when co-administered. No dose adjustments are necessary for patients with normal renal function (see Victrelis® prescribing information).


Zidovudine   Zidovudine: Simultaneous oral administration of clarithromycin immediate-release tablets and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine concentrations. Administration of clarithromycin and zidovudine should be separated by at least two hours [see Pharmacokinetics (12.3)].

The impact of co-administration of clarithromycin extended-release tablets or granules and zidovudine has not been evaluated.


Calcium Channel Blockers:


   
Verapamil Use With Caution Verapamil: Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent verapamil, [see Warnings and Precautions (5.4)].


Amlodipine
Diltiazem


  Amlodipine, Diltiazem: [See Warnings and Precautions (5.4)]
Nifedipine   Nifedipine: Nifedipine is a substrate for CYP3A. Clarithromycin and other macrolides are known to inhibit CYP3A. There is potential of CYP3A-mediated interaction between nifedipine and clarithromycin. Hypotension and peripheral edema were observed when clarithromycin was taken concomitantly with nifedipine [see Warnings and Precautions (5.4)].


Ergot Alkaloids:


   
Ergotamine
Dihydroergotamine
Contraindicated Ergotamine, Dihydroergotamine: Postmarketing reports indicate that coadministration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system [see Contraindications (4.6)].


Gastroprokinetic Agents:


   
Cisapride Contraindicated Cisapride: [See Contraindications (4.2)]


HMG-CoA Reductase Inhibitors:


   
Lovastatin
Simvastatin
Contraindicated Lovastatin, Simvastatin, Atorvastatin, Pravastatin, Fluvastatin: [See Contraindications (4.5)and Warnings and Precautions (5.4)]

Atorvastatin
Pravastatin


Use With Caution  
Fluvastatin

No Dose Adjustment


 
Hypoglycemic Agents:


   
Nateglinide
Pioglitazone
Repaglinide
Rosiglitazone


Use With Caution Nateglinide, Pioglitazone, Repaglinide, Rosiglitazone: [See Warnings and Precautions (5.4)and Adverse Reactions (6.2)]

Insulin   Insulin: [See Warnings and Precautions (5.4) and Adverse Reactions (6.2)]


Immunosuppressants:


   
Cyclosporine Use With Caution Cyclosporine: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with cyclosporine.


Tacrolimus   Tacrolimus: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with tacrolimus.


Phosphodiesterase inhibitors:


   
Sildenafil
Tadalafil
Vardenafil
Use With Caution Sildenafil, Tadalafil, Vardenafil: Each of these phosphodiesterase inhibitors is primarily metabolized by CYP3A, and CYP3A will be inhibited by concomitant administration of clarithromycin. Co-administration of clarithromycin with sildenafil, tadalafil, or vardenafil will result in increased exposure of these phosphodiesterase inhibitors. Co-administration of these phosphodiesterase inhibitors with clarithromycin is not recommended. Increased systemic exposure of these drugs may occur with clarithromycin; reduction of dosage for phosphodiesterase inhibitors should be considered (see their respective prescribing information).


Proton Pump Inhibitors:


   
Omeprazole No Dose Adjustment Omeprazole: The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when coadministered with clarithromycin as a result of increased omeprazole exposures [see Pharmacokinetics (12.3)] (see also Omeprazole under “Drugs That Affect Clarithromycin” in the table below).


Xanthine Derivatives:


   
 
 
Theophylline: Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serum theophylline concentrations [see Pharmacokinetics (12.3)]. Monitoring of serum theophylline concentrations should be considered for patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range.


Triazolobenzodiazepines and Other Related Benzodiazepines:


   
 
Use With Caution Midazolam: When oral midazolam is co-administered with clarithromycin, dose adjustments may be necessary and possible prolongation and intensity of effect should be anticipated [see Warnings and Precautions (5.4)and Pharmacokinetics (12.3)].


Alprazolam
Triazolam
  Triazolam, Alprazolam: Caution and appropriate dose adjustments should be considered when triazolam or alprazolam is co-administered with clarithromycin. There have been postmarketing reports of drug interactions and central nervous system (CNS) effects (e.g., somnolence and confusion) with the concomitant use of clarithromycin and triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested.

In postmarketing experience, erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines.


Temazepam
Nitrazepam
Lorazepam
No Dose Adjustment Temazepam, Nitrazepam, Lorazepam: For benzodiazepines which are not metabolized by CYP3A (e.g., temazepam, nitrazepam, lorazepam), a clinically important interaction with clarithromycin is unlikely.


Cytochrome P450 Inducers:


   
Rifabutin Use With Caution Rifabutin: Concomitant administration of rifabutin and clarithromycin resulted in an increase in rifabutin, and decrease in clarithromycin serum levels together with an increased risk of uveitis (see Rifabutin under “Drugs That Affect Clarithromycin” in the table below).


Other Drugs Metabolized by CYP3A:


   
Alfentanil
Bromocriptine
Cilostazol
Methylprednisole
Vinblastine
Phenobarbital
St. John’s Wort


Use With Caution There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with alfentanil, methylprednisolone, cilostazol, bromocriptine, vinblastine, phenobarbital, and St. John’s Wort.
Other Drugs Metabolized by CYP450 Isoforms Other than CYP3A:


   
Hexobarbital
Phenytoin
Valproate
Use With Caution There have been postmarketing reports of interactions of clarithromycin with drugs not thought to be metabolized by CYP3A, including hexobarbital, phenytoin, and valproate.


Drugs that Affect Clarithromycin
Drug(s) that Affect the Pharmacokinetics of Clarithromycin Recommendation Comments
Antifungals:


   
Itraconazole
 
Itraconazole: Itraconazole may increase the plasma concentrations of clarithromycin. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions (see also Itraconazole under “Drugs That Are Affected By Clarithromycin” in the table above).


Antivirals:


   
Atazanavir Use With Caution Atazanavir: When clarithromycin is co-administered with atazanavir, the dose of clarithromycin should be decreased by 50% [see Clinical Pharmacology (12.3)].

Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with atazanavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium complex. Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.


Ritonavir (in patients with decreased renal function)   Ritonavir: Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with ritonavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium[see Pharmacokinetics (12.3)].

Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.


Saquinavir (in patients with decreased renal function)   Saquinavir: When saquinavir is co-administered with ritonavir, consideration should be given to the potential effects of ritonavir on clarithromycin (refer to ritonavir above) [see Pharmacokinetics (12.3)].


Etravirine   Etravirine: Clarithromycin exposure was decreased by etravirine; however, concentrations of the active metabolite, 14-OH-clarithromycin, were increased. Because 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered; therefore alternatives to clarithromycin should be considered for the treatment of MAC.


Saquinavir (in patients with normal renal function) No Dose Adjustment  
Ritonavir (in patients with normal renal function)


   
Proton Pump Inhibitors:


   
Omeprazole
 
Omeprazole: Clarithromycin concentrations in the gastric tissue and mucus were also increased by concomitant administration of omeprazole [see Pharmacokinetics (12.3)].


Miscellaneous Cytochrome P450 Inducers:


 
Efavirenz
Nevirapine
Rifampicin
Rifabutin
Rifapentine
Use With Caution Inducers of CYP3A enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine will increase the metabolism of clarithromycin, thus decreasing plasma concentrations of clarithromycin, while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. Alternative antibacterial treatment should be considered when treating patients receiving inducers of CYP3A. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with rifabutin (see Rifabutin under “Drugs That Are Affected By Clarithromycin” in the table above).




Table name:
 Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
 Interacting Agents  Prescribing Recommendations
 Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)  Avoid atorvastatin
 HIV protease inhibitor (lopinavir plus ritonavir)  Use with caution and lowest dose necessary
 Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)  Do not exceed 20 mg atorvastatin daily
 HIV protease inhibitor (nelfinavir)
Hepatitis C Protease inhibitor (boceprevir)
 Do not exceed 40 mg atorvastatin daily


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.11, 7.3)


Table name:
AED Coadministered AED Concentration Topiramate Concentration
Phenytoin NC or 25% increase a 48% decrease
Carbamazepine (CBZ) NC 40% decrease
CBZ epoxide b NC NE
Valproic acid 11% decrease 14% decrease
Phenobarbital NC NE
Primidone NC NE
Lamotrigine NC at TPM doses up to 400 mg/day 13% decrease


Table name:
Table 18. Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
*Change relative to reference
Coadministered Drug
 
Dosing Schedule
Effect on Active Moiety
(Risperidone + 9- Hydroxy-
Risperidone (Ratio*)
Risperidone Dose
Recommendation
Coadministered Drug
Risperidone
AUC
Cmax
Enzyme (CYP2D6) inhibitors
 
 
 
 
Fluoxetine
20 mg/day
2 or 3 mg twice daily
1.4
1.5

Re-evaluate dosing.
Do not exceed 8 mg/day
Paroxetine
10 mg/day
4 mg/day
1.3
-

Re-evaluate dosing.
Do not exceed 8 mg/day
20 mg/day
4 mg/day
1.6
-
40 mg/day
4 mg/day
1.8
-
Enzyme (CYP3A/ PgP inducers) Inducers
 
 
 
 
 
Carbamazepine
573 ± 168 mg/day
 
3 mg twice daily
 
0.51
 
0.55
 

Titrate dose upwards.
Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) inhibitors
 
 
 
 
 
Ranitidine
150 mg twice daily
1 mg single dose
1.2
1.4
Dose adjustment not needed
Cimetidine
400 mg twice daily
1 mg single dose
1.1
1.3
Dose adjustment not needed
Erythromycin
500 mg four times daily
1 mg single dose
1.1
0.94
Dose adjustment not needed
Other Drugs
 
 
 
 
 
Amitriptyline
50 mg twice daily
3 mg twice daily
1.2
1.1
Dose adjustment not Needed


Table name:
Interacting  Drug
Interaction

Multivalent cation-containing products including antacids, metal cation or didanosine


Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. 




Warfarin
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)

Antidiabetic agent

Carefully monitor blood glucose (5.11, 7.3)


Table name:
Table 5: Significant Drug Interactions with BUTRANS
Benzodiazepines
Clinical Impact: There have been a number of reports regarding coma and death associated with the misuse and abuse of the combination of buprenorphine and benzodiazepines. In many, but not all of these cases, buprenorphine was misused by self-injection of crushed buprenorphine tablets. Preclinical studies have shown that the combination of benzodiazepines and buprenorphine altered the usual ceiling effect on buprenorphine-induced respiratory depression, making the respiratory effects of buprenorphine appear similar to those of full opioid agonists.
Intervention: Closely monitor patients with concurrent use of BUTRANS and benzodiazepines. Warn patients that it is extremely dangerous to self-administer benzodiazepines while taking BUTRANS, and warn patients to use benzodiazepines concurrently with BUTRANS only as directed by their physician.
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact: Due to additive pharmacologic effects, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.4)].
Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Inhibitors of CYP3A4
Clinical Impact: The concomitant use of buprenorphine and CYP3A4 inhibitors can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of BUTRANS is achieved.

After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the buprenorphine plasma concentration will decrease [see Clinical Pharmacology (12.3)], potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to buprenorphine.
Intervention: If concomitant use is necessary, consider dosage reduction of BUTRANS until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals.

If a CYP3A4 inhibitor is discontinued, consider increasing the BUTRANS dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)
CYP3A4 Inducers
Clinical Impact: The concomitant use of buprenorphine and CYP3A4 inducers can decrease the plasma concentration of buprenorphine [see Clinical Pharmacology (12.3)], potentially resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine.

After stopping a CYP3A4 inducer, as the effects of the inducer decline, the buprenorphine plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both therapeutic effects and adverse reactions and may cause serious respiratory depression.
Intervention: If concomitant use is necessary, consider increasing the BUTRANS dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.

If a CYP3A4 inducer is discontinued, consider BUTRANS dosage reduction and monitor for signs of respiratory depression.
Examples: Rifampin, carbamazepine, phenytoin
Serotonergic Drugs
Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue BUTRANS if serotonin syndrome is suspected.
Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)]
Intervention: The use of BUTRANS is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples: phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist Opioid Analgesics
Clinical Impact: May reduce the analgesic effect of BUTRANS and/or precipitate withdrawal symptoms.
Intervention: Avoid concomitant use.
Examples: butorphanol, nalbuphine, pentazocine
Muscle Relaxants
Clinical Impact: Buprenorphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention: Monitor patients receiving muscle relaxants and BUTRANS for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of BUTRANS and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact: The concomitant use of opioid analgesics, including buprenorphine, and anticholinergic drugs may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when BUTRANS is used concomitantly with anticholinergic drugs.


Table name:

Figure 5: Mean Standing Systolic Blood Pressure Change from Baseline


Table name:
Drugs That Interfere with Hemostasis
Clinical Impact: • Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of naproxen or naproxen sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: Concomitant use of naproxen or naproxen sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen or naproxen sodium is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE-inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: • During concomitant use of naproxen or naproxen sodium and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of naproxen or naproxen sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen or naproxen sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact: The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of naproxen or naproxen sodium and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen or naproxen sodium and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of naproxen or naproxen sodium and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of naproxen or naproxen sodium and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of naproxen or naproxen sodium and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of naproxen or naproxen sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of naproxen or naproxen sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact: Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention: Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen or naproxen sodium is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed release tablets are not recommended.
Cholestyramine
Clinical Impact: Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention: Concomitant administration of cholestyramine with naproxen or naproxen sodium is not recommended.
Probenecid
Clinical Impact: Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention: Patients simultaneously receiving naproxen or naproxen sodium and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact: Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention: Patients simultaneously receiving naproxen or naproxen sodium and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Table 3 Established and Other Potentially SignificantThis table is not all inclusive. Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
Concomitant Drug Class: Drug Name Effect Clinical Comment
HIV antiviral agents
Protease inhibitor:
  atazanavir
↓atazanavir
↑ tenofovir
Coadministration of atazanavir with ATRIPLA is not recommended. Coadministration of atazanavir with either efavirenz or tenofovir DF decreases plasma concentrations of atazanavir. The combined effect of efavirenz plus tenofovir DF on atazanavir plasma concentrations is not known. Also, atazanavir has been shown to increase tenofovir concentrations. There are insufficient data to support dosing recommendations for atazanavir or atazanavir/ritonavir in combination with ATRIPLA.
Protease inhibitor:
  fosamprenavir calcium
↓ amprenavir Fosamprenavir (unboosted): Appropriate doses of fosamprenavir and ATRIPLA with respect to safety and efficacy have not been established.
Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when ATRIPLA is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when ATRIPLA is administered with fosamprenavir plus ritonavir twice daily.
Protease inhibitor:
  indinavir
↓ indinavir The optimal dose of indinavir, when given in combination with efavirenz, is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to efavirenz.
Protease inhibitor:
  lopinavir/ritonavir
↓ lopinavir
↑ tenofovir
Do not use once daily administration of lopinavir/ritonavir. Dose increase of lopinavir/ritonavir is recommended for all patients when coadministered with efavirenz. Refer to the full prescribing information for lopinavir/ritonavir for guidance on coadministration with efavirenz- or tenofovir-containing regimens, such as ATRIPLA. Patients should be monitored for tenofovir-associated adverse reactions.
Protease inhibitor:
  ritonavir
↑ ritonavir
↑ efavirenz
When ritonavir 500 mg every 12 hours was coadministered with efavirenz 600 mg once daily, the combination was associated with a higher frequency of adverse clinical experiences (e.g., dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when ATRIPLA is used in combination with ritonavir.
Protease inhibitor:
  saquinavir
↓ saquinavir Appropriate doses of the combination of efavirenz and saquinavir/ritonavir with respect to safety and efficacy have not been established.
CCR5 co-receptor antagonist:
  maraviroc
↓ maraviroc Efavirenz decreases plasma concentrations of maraviroc. Refer to the full prescribing information for maraviroc for guidance on coadministration with ATRIPLA.
NRTI:
  didanosine
↑ didanosine Coadministration of ATRIPLA and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse reactions including pancreatitis, lactic acidosis, and neuropathy. A dose reduction of didanosine is recommended when coadministered with tenofovir DF. For additional information on coadministration with tenofovir DF-containing products, please refer to the didanosine prescribing information.
NNRTI:
  Other NNRTIs
↑ or ↓ efavirenz and/or NNRTI Combining two NNRTIs has not been shown to be beneficial. ATRIPLA contains efavirenz and should not be coadministered with other NNRTIs.
Integrase strand transfer inhibitor:
  raltegravir
↓ raltegravir Efavirenz reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.
Hepatitis C antiviral agents
Protease inhibitor:
  boceprevir
↓ boceprevir Plasma trough concentrations of boceprevir were decreased when boceprevir was coadministered with efavirenz, which may result in loss of therapeutic effect. The combination should be avoided.
Protease inhibitor:
  simeprevir
↓ simeprevir
↔ efavirenz
Concomitant administration of simeprevir with efavirenz is not recommended because it may result in loss of therapeutic effect of simeprevir.
NS5A inhibitor/NS5B polymerase inhibitor :
  ledipasvir/sofosbuvir
↑ tenofovir Patients receiving ATRIPLA and HARVONI™ (ledipasvir/sofosbuvir) concomitantly should be monitored for adverse reactions associated with tenofovir DF.
Other agents
Anticoagulant:
  warfarin
↑ or ↓ warfarin Plasma concentrations and effects potentially increased or decreased by efavirenz.
Anticonvulsants:
  carbamazepine
↓ carbamazepine
↓ efavirenz
There are insufficient data to make a dose recommendation for ATRIPLA. Alternative anticonvulsant treatment should be used.
  phenytoin
  phenobarbital
↓ anticonvulsant
↓ efavirenz
Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted.
Antidepressants:
  bupropion
↓ buproprion The effect of efavirenz on bupropion exposure is thought to be due to the induction of bupropion metabolism. Increases in bupropion dosage should be guided by clinical response, but the maximum recommended dose of bupropion should not be exceeded.
  sertraline ↓ sertraline Increases in sertraline dose should be guided by clinical response.
Antifungals:
  itraconazole
↓ itraconazole
↓ hydroxy-itraconazole
Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered.
  ketoconazole ↓ ketoconazole Drug interaction trials with ATRIPLA and ketoconazole have not been conducted. Efavirenz has the potential to decrease plasma concentrations of ketoconazole.
  posaconazole ↓ posaconazole Avoid concomitant use unless the benefit outweighs the risks.
Anti-infective:
  clarithromycin
↓ clarithromycin
↑ 14-OH metabolite
Clinical significance unknown. In uninfected volunteers, 46% developed rash while receiving efavirenz and clarithromycin. No dose adjustment of ATRIPLA is recommended when given with clarithromycin. Alternatives to clarithromycin, such as azithromycin, should be considered. Other macrolide antibiotics, such as erythromycin, have not been studied in combination with ATRIPLA.
Antimycobacterial:
  rifabutin
↓ rifabutin Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week.
  rifampin ↓ efavirenz If ATRIPLA is coadministered with rifampin to patients weighing 50 kg or more, an additional 200 mg/day of efavirenz is recommended.
Antimalarials:
  artemether/lumefantrine
↓ artemether
↓ dihydroartemisinin
↓ lumefantrine
Artemether/lumefantrine should be used cautiously with ATRIPLA because decreased artemether, dihydroartemisinin (active metabolite of artemether), and/or lumefantrine concentrations may result in a decrease of antimalarial efficacy of artemether/lumefantrine.
Calcium channel blockers:
  diltiazem
↓ diltiazem
↓ desacetyl diltiazem
↓ N-monodes-methyl diltiazem
Diltiazem dose adjustments should be guided by clinical response (refer to the full prescribing information for diltiazem). No dose adjustment of ATRIPLA is necessary when administered with diltiazem.
  Others (e.g., felodipine, nicardipine, nifedipine, verapamil) ↓ calcium channel blocker No data are available on the potential interactions of efavirenz with other calcium channel blockers that are substrates of CYP3A. The potential exists for reduction in plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response (refer to the full prescribing information for the calcium channel blocker).
HMG-CoA reductase inhibitors:
  atorvastatin
  pravastatin
  simvastatin
↓ atorvastatin
↓ pravastatin
↓ simvastatin
Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased with efavirenz. Consult the full prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose.
Hormonal contraceptives:
Oral:
  ethinyl
  estradiol/norgestimate
↓ active metabolites of norgestimate A reliable method of barrier contraception must be used in addition to hormonal contraceptives. Efavirenz had no effect on ethinyl estradiol concentrations, but progestin levels (norelgestromin and levonorgestrel) were markedly decreased. No effect of ethinyl estradiol/norgestimate on efavirenz plasma concentrations was observed.
Implant:
  etonogestrel
↓ etonogestrel A reliable method of barrier contraception must be used in addition to hormonal contraceptives. The interaction between etonogestrel and efavirenz has not been studied. Decreased exposure of etonogestrel may be expected. There have been postmarketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients.
Immunosuppressants:
  cyclosporine, tacrolimus, sirolimus, and others metabolized by CYP3A
↓ immuno-suppressant Decreased exposure of the immunosuppressant may be expected due to CYP3A induction by efavirenz. These immunosuppressants are not anticipated to affect exposure of efavirenz. Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with ATRIPLA.
Narcotic analgesic:
  methadone
↓ methadone Coadministration of efavirenz in HIV-1 infected individuals with a history of injection drug use resulted in decreased plasma levels of methadone and signs of opiate withdrawal. Methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms. Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms.


Table name:
Muscle Relaxants
Clinical Impact: Morphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Morphine Sulfate Injection and/or the muscle relaxant as necessary.
Cimetidine
Clinical Impact: The concomitant administration of morphine sulfate and cimetidine has been reported to precipitate apnea, confusion and muscle twitching in an isolated report.
Intervention: Monitor patients for increased respiratory and CNS depression when receiving cimetidine concomitantly with Morphine Sulfate Injection.
Diuretics
Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when Morphine Sulfate Injection is used concomitantly with anticholinergic drugs.


Table name:
Table 2. Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T4 and T3 serum transport - but FT4 concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors
(SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
  Interacting Agents   Prescribing Recommendations
  Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)  Avoid atorvastatin
 HIV protease inhibitor (lopinavir plus ritonavir)  Use with caution and lowest dose necessary
  Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)  Do not exceed 20 mg atorvastatin daily
 HIV protease inhibitor (nelfinavir), Hepatitis C Protease inhibitor (boceprevir)  Do not exceed 40 mg atorvastatin daily


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Interacting Agent Examples
Drugs that may increase phenytoin serum levels
Antiepileptic drugs Ethosuximide, felbamate, oxcarbazepine, methsuximide, topiramate
Azoles Fluconazole, ketoconazole, itraconazole, miconazole, voriconazole
Antineoplastic agents Capecitabine, fluorouracil
Antidepressants Fluoxetine, fluvoxamine, sertraline
Gastric acid reducing agents H2 antagonists (cimetidine), omeprazole
Sulfonamides Sulfamethizole, sulfaphenazole, sulfadiazine, sulfamethoxazole trimethoprim
Other Acute alcohol intake, amiodarone, chloramphenicol, chlordiazepoxide, disulfiram, estrogen, fluvastatin, isoniazid, methylphenidate, phenothiazines, salicylates, ticlopidine, tolbutamide, trazodone, warfarin
Drugs that may decrease phenytoin serum levels
Antineoplastic agents usually in combination Bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate
Antiviral agents Fosamprenavir, nelfinavir, ritonavir
Antiepileptic drugs Carbamazepine, vigabatrin
Other Chronic alcohol abuse, diazepam, diazoxide, folic acid, reserpine, rifampin, St. John’s wortb, theophylline
Drugs that may either increase or decrease phenytoin serum levels
Antiepileptic drugs Phenobarbital, valproate sodium, valproic acid


Table name:
Drugs That Interfere with Hemostasis
Clinical Impact: • Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of naproxen or naproxen sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: Concomitant use of naproxen or naproxen sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen or naproxen sodium is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE-inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: • During concomitant use of naproxen or naproxen sodium and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of naproxen or naproxen sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen or naproxen sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact: The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of naproxen or naproxen sodium and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen or naproxen sodium and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of naproxen or naproxen sodium and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of naproxen or naproxen sodium and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of naproxen or naproxen sodium and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of naproxen or naproxen sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of naproxen or naproxen sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact: Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention: Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen or naproxen sodium is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed release tablets are not recommended.
Cholestyramine
Clinical Impact: Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention: Concomitant administration of cholestyramine with naproxen or naproxen sodium is not recommended.
Probenecid
Clinical Impact: Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention: Patients simultaneously receiving naproxen or naproxen sodium and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact: Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention: Patients simultaneously receiving naproxen or naproxen sodium and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
↓ = Decreased (induces lamotrigine glucuronidation).
↑ = Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
Concomitant  Drug
Effect  on  Concentration  of  Lamotrigine  or  Concomitant  Drug
Clinical  Comment
Estrogen-containing oral contraceptive 
preparations containing 30 mcg 
ethinylestradiol and 150 mcg levonorgestrel 
↓lamotrigine



↓levonorgestrel
Decreased lamotrigine concentrations approximately 50%.



Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide 
↓ lamotrigine


? carbamazepine epoxide
Addition of carbamazepine decreases lamotrigine
concentration approximately 40%.

May increase carbamazepine epoxide levels
Lopinavir/ ritonavir
↓ lamotrigine
Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir
↓ lamotrigine
Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone 
↓ lamotrigine
Decreased lamotrigine concentration approximately 40%.

Phenytoin
↓ lamotrigine
Decreased lamotrigine concentration approximately 40%.
Rifampin
↓ lamotrigine
Decreased lamotrigine AUC
approximately 40%.
Valproate 
↑ lamotrigine

? valproate
Increased lamotrigine concentrations slightly more than 2-fold.
There are conflicting study results regarding effect
of lamotrigine on valproate concentrations: 1) a
mean 25% decrease in valproate concentrations in
healthy volunteers, 2) no change in valproate
concentrations in controlled clinical trials in
patients with epilepsy.


Table name:
blood dyscrasias —    diarrhea      hyperthyroidism
   see  CONTRAINDICATIONS  elevated temperature   poor nutritional state    
cancer  hepatic disorders   steatorrhea
collagen vascular disease     infectious hepatitis   vitamin K deficiency
congestive heart failure     jaundice


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C Protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Table 8: Clinically Significant Drug Interactions with LANTUS
Drugs That May Increase the Risk of Hypoglycemia
Drugs: Antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, propoxyphene, salicylates, somatostatin analogs (e.g., octreotide), and sulfonamide antibiotics.
Intervention: Dose reductions and increased frequency of glucose monitoring may be required when LANTUS is co-administered with these drugs.
Drugs That May Decrease the Blood Glucose Lowering Effect of LANTUS
Drugs: Atypical antipsychotics (e.g., olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones
Intervention: Dose increases and increased frequency of glucose monitoring may be required when LANTUS is co-administered with these drugs.
Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of LANTUS
Drugs: Alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia.
Intervention: Dose adjustment and increased frequency of glucose monitoring may be required when LANTUS is co-administered with these drugs.
Drugs That May Blunt Signs and Symptoms of Hypoglycemia
Drugs: beta-blockers, clonidine, guanethidine, and reserpine
Intervention: Increased frequency of glucose monitoring may be required when LANTUS is co-administered with these drugs.


Table name:
Factors Dosage Adjustments for Aripiprazole
Known CYP2D6 Poor Metabolizers Administer half of usual dose
Known CYP2D6 Poor Metabolizersand strong CYP3A4 inhibitors Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors Administer half of usual dose
Strong CYP2D6 and CYP3A4inhibitors Administer a quarter of usual dose
Strong CYP3A4 inducers Double usual dose over 1 to 2 weeks


Table name:
Interacting  Drug 
Interaction 
Multivalent cation-containing products including antacids, metal cations or didanosine 
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin 
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents 
Carefully monitor blood glucose (5.11, 7.3)


Table name:
Drug Interactions Associated with Increased Risk of  Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice Avoid grapefruit juice


Table name:
Table 18Summary of Effect of Coadministered Drugs on Exposure to Active Moiety(Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients withSchizophrenia
*Change relative to reference
Coadministered Drug
Dosing Schedule

Effect on Active
Moiety
(Risperidone + 9-
Hydroxy-
Risperidone (Ratio*)

Risperidone Dose
Recommendation

Coadministered Drug
Risperidone
AUC
Cm a x

Enzyme (CYP2D6) 
Inhibitors 





Fluoxetine 
20 mg/day
2 or 3 mg twice
daily
1.4
1.5
Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine 
10 mg/day
4 mg/day
1.3
-
Re-evaluate dosing. 

20 mg/day
4 mg/day
1.6
-
Do not exceed 8 mg/day

40 mg/day
4 mg/day
1.8
-

Enzyme (CYP3A/ 
PgP inducers) 





Carbamazepine 
573 ± 168 mg/day
3 mg twice daily
0.51
0.55
Titrate dose upwards.
Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) 
Inhibitors 





Ranitidine 
150 mg twice daily
1 mg single dose
1.2
1.4
Dose adjustment not
needed
Cimetidine 
400 mg twice daily
1 mg single dose
1.1
1.3
Dose adjustment not
needed
Erythromycin 
500 mg four times
daily
1 mg single dose
1.1
0.94
Dose adjustment not
needed
Other Drugs 





Amitriptyline 
50 mg twice daily
3 mg twice daily
1.2
1.1
Dose adjustment not
needed


Table name:
Table 2: Examples of CYP450 Interactions with Warfarin
 Enzyme  Inhibitors  Inducers
 CYP2C9  amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast  aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
 CYP1A2  acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton  montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
 CYP3A4  alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton  armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Intervention:
Monitor patients with concomitant use of naproxen with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact:
Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:
Concomitant use of naproxen and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:
• NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).
• In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:
• During concomitant use of naproxen and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.
• During concomitant use of naproxen and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia).
When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:
Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention
During concomitant use of naproxen with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).


Table name:
Table 7: Summary of AED Interactions with Oxcarbazepine
AED Coadministered Dose of AED (mg/day) Oxcarbazepine Dose (mg/day) Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval) Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine 400 to 2000 900 nc nc denotes a mean change of less than 10% 40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital 100 to 150 600 to 1800 14% increase [CI: 2% increase, 24% increase] 25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin 250 to 500 600 to 1800 >1200 to 2400 nc , Pediatrics up to 40% increase Mean increase in adults at high oxcarbazepine doses [CI: 12% increase, 60% increase] 30% decrease [CI: 3% decrease, 48% decrease]
Valproic acid 400 to 2800 600 to 1800 nc 18% decrease [CI: 13% decrease, 40% decrease]


Table name:
Table 18Summary of Effect of Coadministered Drugs on Exposure to Active Moiety(Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients withSchizophrenia
*Change relative to reference
Coadministered Drug
Dosing Schedule
Effect on Active
Moiety
(Risperidone + 9-
Hydroxy-
Risperidone (Ratio*)
Risperidone Dose
Recommendation
Coadministered Drug
Risperidone
AUC
Cmax
Enzyme (CYP2D6) 
Inhibitors 
Fluoxetine 
20 mg/day
2 or 3 mg twice
daily
1.4
1.5
Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine 
10 mg/day
4 mg/day
1.3
-
Re-evaluate dosing. 
20 mg/day
4 mg/day
1.6
-
Do not exceed 8 mg/day
40 mg/day
4 mg/day
1.8
-
Enzyme (CYP3A/ 
PgP inducers) 
Carbamazepine 
573 ± 168 mg/day
3 mg twice daily
0.51
0.55
Titrate dose upwards.
Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) 
Inhibitors 
Ranitidine 
150 mg twice daily
1 mg single dose
1.2
1.4
Dose adjustment not
needed
Cimetidine 
400 mg twice daily
1 mg single dose
1.1
1.3
Dose adjustment not
needed
Erythromycin 
500 mg four times
daily
1 mg single dose
1.1
0.94
Dose adjustment not
needed
Other Drugs 
Amitriptyline 
50 mg twice daily
3 mg twice daily
1.2
1.1
Dose adjustment not
needed


Table name: Clinical Impact: Indomethacin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of indomethacin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of indomethacin with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ see Warnings and Precautions ( 5.11 )]. Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ see Warnings and Precautions ( 5.2 ) ]. Intervention: Concomitant use of indomethacin capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions ( 5.11 )].Indomethacin is not a substitute for low dose aspirin for cardiovascular protection. Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention: During concomitant use of indomethacin capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.During concomitant use of indomethacin capsules and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ see Warnings and Precautions ( 5.6 )].When these drugs are administered concomitantly, patients should be adequately hydrated.  Assess renal function at the beginning of the concomitant treatment and periodically thereafter. Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.It has been reported that the addition of triamterene to a maintenance schedule of Indomethacin resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin and triamterene should not be administered together.Both indomethacin and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently [ see Warnings and Precautions ( 5.6 )].   Intervention: Indomethacin and triamterene should not be administered together. During concomitant use of indomethacin capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects. Be aware that indomethacin and potassium-sparing diuretics may both be associated with increased serum potassium levels. [ see Warnings and Precautions ( 5.6 )].     Clinical Impact: The concomitant use of indomethacin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.   Intervention: During concomitant use of indomethacin capsules and digoxin, monitor serum digoxin levels.     Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.   Intervention: During concomitant use of indomethacin capsules and lithium, monitor patients for signs of lithium toxicity.     Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).   Intervention: During concomitant use of indomethacin capsules and methotrexate, monitor patients for methotrexate toxicity.     Clinical Impact: Concomitant use of indomethacin capsules and cyclosporine may increase cyclosporine's nephrotoxicity.   Intervention: During concomitant use of indomethacin capsules and cyclosporine, monitor patients for signs of worsening renal function.     Clinical Impact: Concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ see Warnings and Precautions ( 5.2 )]. Combined use with diflunisal may be particularly hazardous because diflunisal causes significantly higher plasma levels of indomethacin [see Clinical Pharmacology ( 12.3 )].In some patients, combined use of indomethacin and diflunisal has been associated with fatal gastrointestinal hemorrhage.   Intervention: The concomitant use of indomethacin with other NSAIDs or salicylates, especially diflunisal, is not recommended.     Clinical Impact: Concomitant use of indomethacin capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).   Intervention: During concomitant use of indomethacin capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.     Clinical Impact: When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased.   Intervention: During the concomitant use of indomethacin and probenecid, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect.  When increases in the dose of indomethacin are made, they should be made carefully and in small increments.  
Drugs That Interfere with Hemostasis
 
 
 
 
Aspirin
 
 
 
 
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
 
 
 
 
Diuretics
 
 
 
 
 
 
Digoxin
 
 
 
 
 
 
 
Lithium
 
 
 
 
 
 
 
Methotrexate
 
 
 
 
 
 
 
Cyclosporine
 
 
 
 
 
 
 
NSAIDs and Salicylates
 
 
 
 
 
 
 
Pemetrexed
 
 
 
 
 
 
 
Probenecid
 
 
 
 
 
 
 


Table name:
Table 3: Clinically Significant Drug Interactions with Celecoxib
   Drugs That Interfere w ith Hemostasis
 Clinical Impact:
  Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of Celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
 Intervention:
 Monitor patients with concomitant use of celecoxib with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11) ].
   Aspirin
 Clinical Impact:
 Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2) ].
In two studies in healthy volunteers, and in patients with osteoarthritis and established heart disease respectively, celecoxib (200 to 400 mg daily) has demonstrated a lack of interference with the cardioprotective antiplatelet effect of aspirin (100 to 325 mg).
 Intervention:
 Concomitant use of celecoxib and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11) ].
Celecoxib is not a substitute for low dose aspirin for cardiovascular protection.
   ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
 Clinical Impact:
  NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
 Intervention:
  During concomitant use of celecoxib and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of celecoxib and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6) ]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
   Diuretics
 Clinical Impact:
 Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
 Intervention:
 During concomitant use of celecoxib with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6) ].
   Digoxin
 Clinical Impact:
 The concomitant use of Celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
 Intervention:
 During concomitant use of celecoxib and digoxin, monitor serum digoxin levels.
   Lithium
 Clinical Impact:
 NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
 Intervention:
 During concomitant use of celecoxib and lithium, monitor patients for signs of lithium toxicity.
   Methotrexate
 Clinical Impact:
 Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Celecoxib has no effect on methotrexate pharmacokinetics.
 Intervention:
 During concomitant use of celecoxib and methotrexate, monitor patients for methotrexate toxicity.
   Cyclosporine
 Clinical Impact:
 Concomitant use of celecoxib and cyclosporine may increase cyclosporine’s nephrotoxicity.
 Intervention:
 During concomitant use of celecoxib and cyclosporine, monitor patients for signs of worsening renal function.
   NSAIDs a nd Salicylates
 Clinical Impact:
 Concomitant use of Celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2) ].
 Intervention:
 The concomitant use of Celecoxib with other NSAIDs or salicylates is not recommended.
  Pemetrexed
 Clinical Impact:
 Concomitant use of celecoxib and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
 Intervention:
 During concomitant use of celecoxib and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.
NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.
In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
  CYP2C9 Inhibitors or inducers
 Clinical Impact:
 Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Co­-administration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of celecoxib.
 Intervention
 Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers. [see Clinical Pharmacology (12.3) ].
   CYP2D6 substrates
 Clinical Impact:
 In vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6 (e.g. atomoxetine), and celecoxib may enhance the exposure and toxicity of these drugs.
 Intervention
 Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2D6 substrates. [see Clinical Pharmacology (12.3) ].
   Corticosteroids
 Clinical Impact:
 Concomitant use of corticosteroids with celecoxib may increase the risk of GI ulceration or bleeding.
 Intervention
 Monitor patients with concomitant use of celecoxib with corticosteroids for signs of bleeding [see Warnings and Precautions (5.2) ].


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Do not exceed 40 mg atorvastatin daily


Table name:
Table 13 Established and Other Potentially Significant Drug Interactions
Concomitant  Drug
Effect  on  Concentration  of  Lamotrigine  or  Concomitant  Drug
Clinical  Comment
↓ = Decreased (induces lamotrigine glucuronidation).
↑ = Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel
↓ lamotrigine
Decreased lamotrigine concentrations approximately 50%.

↓ levonorgestrel
Decrease in levonorgestrel component by 19%.
Carbamazepine and epoxide
↓ lamotrigine
Addition of carbamazepine decreases lamotrigine concentration approximately 40%.

? Carbamazepine 
 epoxide
May increase 
Carbamazepine epoxide levels.
Lopinavir/ritonavir 
↓ lamotrigine 
Decreased lamotrigine concentration approximately 50%. 
Atazanavir/ritonavir 
↓ lamotrigine 
Decreased lamotrigine AUC approximately 32%. 
Phenobarbital/Primidone
↓ lamotrigine
Decreased lamotrigine concentration approximately 40%.
Phenytoin
↓ lamotrigine
Decreased lamotrigine concentration approximately 40%.
Rifampin
↓ lamotrigine
Decreased lamotrigine AUC approximately 40%.
Valproate
↑ lamotrigine
Increased lamotrigine concentrations slightly more than 2-fold.

? valproate
There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy. 


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Table 7: Summary of AED Interactions with Oxcarbazepine
AED Coadministered Dose of AED (mg/day) Oxcarbazepine Dose (mg/day) Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval) Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine 400 to 2000 900 ncnc denotes a mean change of less than 10% 40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital 100 to 150 600 to 1800 14% increase [CI: 2% increase, 24% increase] 25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin 250 to 500 600 to 1800 >1200 to 2400 nc , Pediatrics up to 40% increaseMean increase in adults at high oxcarbazepine doses [CI: 12% increase, 60% increase] 30% decrease [CI: 3% decrease, 48% decrease]
Valproic acid 400 to 2800 600 to 1800 nc 18% decrease [CI: 13% decrease, 40% decrease]


Table name:
Drug Effect
Phenylephrine with prior administration of monoamine oxidase inhibitors (MAOI). Cardiac pressor response potentiated. May cause acute hypertensive crisis.
Phenylephrine with tricyclic antidepressants. Pressor response increased.
Phenylephrine with ergot alkaloids. Excessive rise in blood pressure.
Phenylephrine with bronchodilator sympathomimetic agents and with epinephrine or other sympathomimetics. Tachycardia or other arrhythmias may occur.
Phenylephrine with atropine sulfate. Reflex bradycardia blocked; pressor response enhanced.
Phenylephrine with prior administration of propranolol or other ß-adrenergic blockers. Cardiostimulating effects blocked.
Phenylephrine with prior administration of phentolamine or other α-adrenergic blockers. Pressor response decreased.
Phenylephrine with diet preparations, such as amphetamines or phenylpropanolamine. Synergistic adrenergic response.


Table name:
Interacting Drug Interaction
Theophylline Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin Monitor phenytoin level (7)
Methotrexate Monitor for methotrexate toxicity (7)
Cyclosporine May increase serum creatinine. Monitor serum creatinine (7)
Multivalent cation-containing products including antacids, metal cations or didanosine Decreased ciprofloxacin tablets absorption. Take 2 hours before or 6 hours after ciprofloxacin tablets (7)


Table name:
Table 8: Selected Drug Interactions in Adults
Concomitant Drug Class:
Drug Name
Effect on Concentration of Raltegravir Clinical Comment
Metal-Containing Antacids
aluminum and/or magnesium-containing antacids Coadministration or staggered administration of aluminum and/or magnesium hydroxide-containing antacids and ISENTRESS is not recommended.
Other Agents
rifampin The recommended dosage of ISENTRESS is 800 mg twice daily during coadministration with rifampin. There are no data to guide co-administration of ISENTRESS with rifampin in patients below 18 years of age [see Dosage and Administration (2.1)].


Table name:
Table 8: Clinically Significant Drug Interactions with Clarithromycin
Drugs That Are Affected By Clarithromycin
Drug(s) with Pharmacokinetics Affected by Clarithromycin Recommendation Comments
Antiarrhythmics: Disopyramide Quinidine Dofetilide Amiodarone Sotalol Procainamide Digoxin Not Recommended Use With Caution Disopyramide, Quinidine: There have been postmarketing reports of torsades de pointes occurring with concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QTc prolongation during coadministration of clarithromycin with these drugs [see Warnings and Precautions (5.3)]. Serum concentrations of these medications should also be monitored. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with disopyramide and quinidine. There have been postmarketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide. Therefore, blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide. Digoxin: Digoxin is a substrate for P-glycoprotein (Pgp) and clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are coadministered, inhibition of Pgp by clarithromycin may lead to increased exposure of digoxin. Elevated digoxin serum concentrations in patients receiving clarithromycin and digoxin concomitantly have been reported in postmarketing surveillance. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Monitoring of serum digoxin concentrations should be considered, especially for patients with digoxin concentrations in the upper therapeutic range.
Oral Anticoagulants: Warfarin Use With Caution Oral anticoagulants: Spontaneous reports in the postmarketing period suggest that concomitant administration of clarithromycin and oral anticoagulants may potentiate the effects of the oral anticoagulants. Prothrombin times should be carefully monitored while patients are receiving clarithromycin and oral anticoagulants simultaneously [see Warnings and Precautions (5.4)].
Antiepileptics: Carbamazepine Use With Caution Carbamazepine: Concomitant administration of single doses of clarithromycin and carbamazepine has been shown to result in increased plasma concentrations of carbamazepine. Blood level monitoring of carbamazepine may be considered. Increased serum concentrations of carbamazepine were observed in clinical trials with clarithromycin. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with carbamazepine.
Antifungals: Itraconazole Fluconazole Use With Caution No Dose Adjustment Itraconazole: Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when administered concomitantly (see also Itraconazole under “Drugs That Affect Clarithromycin” in the table below). Clarithromycin may increase the plasma concentrations of itraconazole. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions. Fluconazole: [see Pharmacokinetics (12.3)]
Anti-Gout Agents: Colchicine (in patients with renal or hepatic impairment) Colchicine (in patients with normal renal and hepatic function) Contraindicated Use With Caution Colchicine: Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. The dose of colchicine should be reduced when coadministered with clarithromycin in patients with normal renal and hepatic function [see Contraindications (4.4) and Warnings and Precautions (5.4)].
Antipsychotics: Pimozide Quetiapine Contraindicated Pimozide: [see Contraindications (4.2)] Quetiapine: Quetiapine is a substrate for CYP3A4, which is inhibited by clarithromycin. Coadministration with clarithromycin could result in increased quetiapine exposure and possible quetiapine related toxicities. There have been postmarketing reports of somnolence, orthostatic hypotension, altered state of consciousness, neuroleptic malignant syndrome, and QT prolongation during concomitant administration. Refer to quetiapine prescribing information for recommendations on dose reduction if coadministered with CYP3A4 inhibitors such as clarithromycin.
Antispasmodics: Tolterodine (patients deficient in CYP2D6 activity) Use With Caution Tolterodine: The primary route of metabolism for tolterodine is via CYP2D6. However, in a subset of the population devoid of CYP2D6, the identified pathway of metabolism is via CYP3A. In this population subset, inhibition of CYP3A results in significantly higher serum concentrations of tolterodine. Tolterodine 1 mg twice daily is recommended in patients deficient in CYP2D6 activity (poor metabolizers) when coadministered with clarithromycin.
Antivirals: Atazanavir Saquinavir (in patients with decreased renal function) Ritonavir Etravirine Maraviroc Boceprevir (in patients with normal renal function) Didanosine Zidovudine Use With Caution No Dose Adjustment Atazanavir: Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction (see Atazanavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)]. Saquinavir: Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A and there is evidence of a bi-directional drug interaction (see Saquinavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)]. Ritonavir, Etravirine: (see Ritonavir and Etravirine under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)]. Maraviroc: Clarithromycin may result in increases in maraviroc exposures by inhibition of CYP3A metabolism. See Selzentry® prescribing information for dose recommendation when given with strong CYP3A inhibitors such as clarithromycin. Boceprevir: Both clarithromycin and boceprevir are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when coadministered. No dose adjustments are necessary for patients with normal renal function (see Victrelis® prescribing information). Zidovudine: Simultaneous oral administration of clarithromycin immediate-release tablets and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine concentrations. Administration of clarithromycin and zidovudine should be separated by at least two hours [see Pharmacokinetics (12.3)].

The impact of coadministration of clarithromycin extended-release tablets or granules and zidovudine has not been evaluated.
Calcium Channel Blockers: Verapamil Amlodipine Diltiazem Nifedipine Use With Caution Verapamil: Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent verapamil, [see Warnings and Precautions (5.4)]. Amlodipine, Diltiazem: [see Warnings and Precautions (5.4)] Nifedipine: Nifedipine is a substrate for CYP3A. Clarithromycin and other macrolides are known to inhibit CYP3A. There is potential of CYP3A-mediated interaction between nifedipine and clarithromycin. Hypotension and peripheral edema were observed when clarithromycin was taken concomitantly with nifedipine [see Warnings and Precautions (5.4)].
Ergot Alkaloids: Ergotamine Dihydroergotamine Contraindicated Ergotamine, Dihydroergotamine: Postmarketing reports indicate that coadministration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system [see Contraindications (4.6)].
Gastroprokinetic Agents: Cisapride Contraindicated Cisapride: [see Contraindications (4.2)]
HMG-CoA Reductase Inhibitors: Lovastatin Simvastatin Atorvastatin Pravastatin Fluvastatin Contraindicated Use With Caution No Dose Adjustment Lovastatin, Simvastatin, Atorvastatin, Pravastatin, Fluvastatin: [see Contraindications (4.5) and Warnings and Precautions (5.4)]
Hypoglycemic Agents: Nateglinide Pioglitazone Repaglinide Rosiglitazone Insulin Use With Caution Nateglinide, Pioglitazone, Repaglinide, Rosiglitazone: [see Warnings and Precautions (5.4) and Adverse Reactions (6.2)] Insulin: [see Warnings and Precautions (5.4) and Adverse Reactions (6.2)]
Immunosuppressants: Cyclosporine Tacrolimus Use With Caution Cyclosporine: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with cyclosporine. Tacrolimus: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with tacrolimus.
Phosphodiesterase inhibitors: Sildenafil Tadalafil Vardenafil Use With Caution Sildenafil, Tadalafil, Vardenafil: Each of these phosphodiesterase inhibitors is primarily metabolized by CYP3A, and CYP3A will be inhibited by concomitant administration of clarithromycin. Coadministration of clarithromycin with sildenafil, tadalafil, or vardenafil will result in increased exposure of these phosphodiesterase inhibitors. Coadministration of these phosphodiesterase inhibitors with clarithromycin is not recommended. Increased systemic exposure of these drugs may occur with clarithromycin; reduction of dosage for phosphodiesterase inhibitors should be considered (see their respective prescribing information).
Proton Pump Inhibitors: Omeprazole No Dose Adjustment Omeprazole: The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when coadministered with clarithromycin as a result of increased omeprazole exposures [see Pharmacokinetics (12.3)] (see also Omeprazole under “Drugs That Affect Clarithromycin” in the table below).
Xanthine Derivatives: Theophylline Use With Caution Theophylline: Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serum theophylline concentrations [see Pharmacokinetics (12.3)]. Monitoring of serum theophylline concentrations should be considered for patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range.
Triazolobenzodiazepines and Other Related Benzodiazepines: Midazolam Alprazolam Triazolam Temazepam Nitrazepam Lorazepam Use With Caution No Dose Adjustment Midazolam: When oral midazolam is coadministered with clarithromycin, dose adjustments may be necessary and possible prolongation and intensity of effect should be anticipated [see Warnings and Precautions (5.4) and Pharmacokinetics (12.3)]. Triazolam, Alprazolam: Caution and appropriate dose adjustments should be considered when triazolam or alprazolam is coadministered with clarithromycin. There have been postmarketing reports of drug interactions and central nervous system (CNS) effects (e.g., somnolence and confusion) with the concomitant use of clarithromycin and triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested. In postmarketing experience, erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines. Temazepam, Nitrazepam, Lorazepam: For benzodiazepines which are not metabolized by CYP3A (e.g., temazepam, nitrazepam, lorazepam), a clinically important interaction with clarithromycin is unlikely.
Cytochrome P450 Inducers: Rifabutin Use With Caution Rifabutin: Concomitant administration of rifabutin and clarithromycin resulted in an increase in rifabutin, and decrease in clarithromycin serum levels together with an increased risk of uveitis (see Rifabutin under “Drugs That Affect Clarithromycin” in the table below).
Other Drugs Metabolized by CYP3A: Alfentanil Bromocriptine Cilostazol Methylprednisole Vinblastine Phenobarbital St. John’s Wort Use With Caution There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with alfentanil, methylprednisolone, cilostazol, bromocriptine, vinblastine, phenobarbital, and St. John’s Wort.
Other Drugs Metabolized by CYP450 Isoforms Other than CYP3A: Hexobarbital Phenytoin Valproate Use With Caution There have been postmarketing reports of interactions of clarithromycin with drugs not thought to be metabolized by CYP3A, including hexobarbital, phenytoin, and valproate.
Drugs that Affect Clarithromycin
Drug(s) that Affect the Pharmacokinetics of Clarithromycin Recommendation Comments
Antifungals: Itraconazole Use With Caution Itraconazole: Itraconazole may increase the plasma concentrations of clarithromycin. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions (see also Itraconazole under “Drugs That Are Affected By Clarithromycin” in the table above).
Antivirals: Atazanavir Ritonavir (in patients with decreased renal function) Saquinavir (in patients with decreased renal function) Etravirine Saquinavir (in patients with normal renal function) Ritonavir (in patients with normal renal function) Use With Caution No Dose Adjustments Atazanavir: When clarithromycin is coadministered with atazanavir, the dose of clarithromycin should be decreased by 50% [see Clinical Pharmacology (12.3)]. Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is coadministered with atazanavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium complex. Doses of clarithromycin greater than 1000 mg per day should not be coadministered with protease inhibitors. Ritonavir: Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is coadministered with ritonavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium [see Pharmacokinetics (12.3)]. Doses of clarithromycin greater than 1000 mg per day should not be coadministered with protease inhibitors. Saquinavir: When saquinavir is coadministered with ritonavir, consideration should be given to the potential effects of ritonavir on clarithromycin (refer to ritonavir above) [see Pharmacokinetics (12.3)]. Etravirine: Clarithromycin exposure was decreased by etravirine; however, concentrations of the active metabolite, 14-OH-clarithromycin, were increased. Because 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered; therefore alternatives to clarithromycin should be considered for the treatment of MAC.
Proton Pump Inhibitors: Omeprazole Use With Caution Omeprazole: Clarithromycin concentrations in the gastric tissue and mucus were also increased by concomitant administration of omeprazole [see Pharmacokinetics (12.3)].
Miscellaneous Cytochrome P450 Inducers: Efavirenz Nevirapine Rifampicin Rifabutin Rifapentine Use With Caution Inducers of CYP3A enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine will increase the metabolism of clarithromycin, thus decreasing plasma concentrations of clarithromycin, while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. Alternative antibacterial treatment should be considered when treating patients receiving inducers of CYP3A. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with rifabutin (see Rifabutin under “Drugs That Are Affected By Clarithromycin” in the table above).


Table name:
Table 7 Summary of AED Interactions with Oxcarbazepine Tablets, USP
AED Coadministered Dose of AED
(mg/day)
Oxcarbazepine Tablets Dose
(mg/day)
Influence of Oxcarbazepine Tablets on AED Concentration
(Mean Change, 90% Confidence Interval)
Influence of AED on MHD Concentration
(Mean Change, 90% Confidence Interval)
Carbamazepine 400-2000 900 nc nc denotes a mean change of less than 10% 40% decrease
[CI: 17% decrease, 57% decrease]
Phenobarbital 100-150 600-1800 14% increase
[CI: 2% increase, 24% increase]
25% decrease
[CI: 12% decrease, 51% decrease]
Phenytoin 250-500 600-1800
>1200-2400
nc , Pediatrics up to 40% increase Mean increase in adults at high oxcarbazepine tablets, USP doses
[CI: 12% increase, 60% increase]
30% decrease
[CI: 3% decrease, 48% decrease]
Valproic acid 400-2800 600-1800 nc 18% decrease
[CI: 13% decrease, 40% decrease]


Table name:
Table 2: Drug-Thyroidal Axis Interactions
   Drug or Drug Class    Effect
   Drugs that may reduce TSH secretion–the reduction is not sustained; therefore, hypothyroidism does not occur
  Dopamine / Dopamine Agonists
Glucocorticoids
Octreotide
  Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day).
   Drugs that alter thyroid hormone secretion
   Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
  Aminoglutethimide
Amiodarone
Iodide(including iodine-containing
  Radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
  Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients.  The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T 4 and T 3 levels and increase TSH, although all values remain within normal limits in most patients.
   Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
  Amiodarone
Iodide(including iodine-containing   
  Radiographic contrast agents)
  Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma).  Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
   Drugs that may decrease T 4 absorption, which may result in hypothyroidism
  Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
  Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism.  Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents.  Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
   Drugs that may alter T 4 and T 3 serum transport  - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
   Drugs that may increase serum TBG concentration    Drugs that may decrease serum TBG concentration
  Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
  Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
   Drugs that may cause protein-binding site displacement
  Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
  Administration of these agents with levothyroxine results in an initial transient increase in FT 4. Continued administration results in a decrease in serum T 4, and normal FT 4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T 4 and T 3 to TBG and transthyretin. An initial increase in serum FT 4 is followed by return of FT 4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T 4 levels may decrease by as much as 30%.
   Drugs that may alter T 4 and T 3 metabolism
   Drugs that may increase hepatic metabolism, which may result  in hypothyroidism
  Carbamazepine
Hydantoins
Phenobarbital
Rifampin
  Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T 4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
   Drugs that may decrease T 4 5’-deiodinase activity
  Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
  Administration of these enzyme inhibitors decreases the peripheral conversion of T 4 to T 3, leading to decreased T 3 levels. However, serum T 4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T 3 and T 4  levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T 3 concentrations by 30% with minimal change in serum T 4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T 3 and T 4 levels due to decreased TBG production (see above).
   Miscellaneous
  Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
  Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
  Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors
  (SSRIs; e.g., Sertraline)
  Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of  tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
  Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
  Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
  Cardiac Glycosides   Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
  Cytokines
- Interferon-α
- Interleukin-2
  Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
  Growth Hormones
- Somatrem
- Somatropin
  Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
  Ketamine   Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
  Methylxanthine Bronchodilators
- (e.g., Theophylline)
  Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
  Radiographic Agents   Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
  Sympathomimetics   Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
  Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
  These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.


Table name:
Drugs that Affect Renal Function
A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDS], COX-2 inhibitors may impair the excretion of digoxin.
Antiarrthymics
Dofetilide
Concomitant administration with digoxin was associated with  a higher rate of torsades de pointes
Sotalol
Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
Dronedarone
Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone Analog
Teriparatide
Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement
Thyroid Supplement
Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics
Epinephrine
Norepinephrine
Dopamine
Can increase the risk of cardiac arrhythmias
Neuromuscular Blocking Agents
Succinylcholine
May cause sudden extrusion of potassium from muscle cells causing arrhythmias inpatients taking digoxin.
Supplements
Calcium
If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.
Hyperpolarization-activated cyclic nucleotide-gated channel blocker  Ivabradine Can increase the risk of bradycardia.


Table name:
Concomitant Drug Name Effect of Carbamazepine on Other Drugs Clinical Recommendation
Boceprevir Decrease in boceprevir levels Coadministration of carbamazepine with boceprevir is contraindicated
Acetaminophen, albendazole, alprazolam, aprepitant, buprenorphone, bupropion, citalopram, clonazepam, clozapine, corticosteroids (e.g., prednisolone, dexamethasone), cyclosporine, dicumarol, dihydropyridine calcium channel blockers (e.g., felodipine), doxycycline, ethosuximide, everolimus, haloperidol, imatinib, itraconazole, lamotrigine, levothyroxine, methadone, methsuximide, mianserin, midazolam, olanzapine, oral and other hormonal contraceptives, oxcarbazepine, paliperidone, phensuximide, phenytoin, praziquantel, protease inhibitors, risperidone, sertraline, sirolimus, tadalafil, theophylline, tiagabine, topiramate, tramadol, trazodone, tricyclic antidepressants (e.g., imipramine, amitriptyline, nortriptyline), valproate, warfarin, ziprasidone, zonisamide Decrease in concomitant drug levels Monitor the concentration and consider a dosage adjustment of the concomitant drug(s)
Cyclophosphamide Increase in cyclo-phosphamide levels (potential for increased toxicity) Monitor for signs of increased cyclophosphamide toxicity
Aripiprazole Decrease in aripiprazole levels When carbamazepine is added to aripiprazole, the aripiprazole dose should be doubled; additional dose increases should be based on clinical evaluation; when carbamazepine is withdrawn from the combination therapy, the aripiprazole dose should be reduced
Tacrolimus Decrease in tacrolimus levels Monitor tacrolimus blood concentrations and make appropriate dosage adjustments
Temsirolimus Decrease in temsirolimus levels The use of concomitant strong CYP3A4 inducers such as carbamazepine should be avoided with temsirolimus; if carbamazepine must be coadministered with temsirolimus, consider adjusting the dosage of temsirolimus
Lapatinib Decrease in lapatinib levels The use of carbamazepine with lapatinib should generally be avoided; dosage adjustment should be considered if lapatinib is coadministered with carbamazepine; if carbamazepine is started in a patient already taking lapatinib, the dose of lapatinib should be gradually titrated up; if carbamazepine is discontinued, the lapatinib dose should be reduced
Nefazodone Decrease in nefazodone levels Coadministration of carbamazepine with nefazodone is contraindicated
Valproate Decrease in valproate levels Monitor valproate concentrations when carbamazepine is introduced or withdrawn in patients using valproic acid


Table name:
Table 2: Examples of CYP450 Interactions with Warfarin
 Enzyme  Inhibitors  Inducers
 CYP2C9  amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast  aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
 CYP1A2  acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton  montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
 CYP3A4  alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton  armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Concomitant Drug Name or Drug Class Clinical Rationale Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) The concomitant use of aripiprazole with strong CYP3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)]. With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin) The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)]. With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Antihypertensive Drugs Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.8)].
Benzodiazepines(e.g., lorazepam) The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.8)]. Monitor sedation and blood pressure. Adjust dose accordingly.


Table name:
Drug/Drug Class (Mechanism of Interaction by Voriconazole) Drug Plasma Exposure
(Cmax and AUCτ)
Recommendations for Drug Dosage Adjustment/Comments
Sirolimus*
(CYP3A4 Inhibition)
Significantly Increased Contraindicated
Rifabutin*
(CYP3A4 Inhibition)
Significantly Increased Contraindicated
Efavirenz (400 mg q 24h)**
(CYP3A4 Inhibition)
Efavirenz (300 mg q 24h) ** (CYP3A4 Inhibition)
Significantly Increased Slight Increased in AUCt Contraindicated When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)**(CYP3A4 Inhibition) Low-dose Ritonavir (100 mg q12h)** No Significant Effect of Voriconazole on Ritonavir Cmax or AUCτ Slight Decrease in Ritonavir Cmax and AUCτ Contraindicated because of significant reduction of voriconazole Cmax and AUCτ
Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole Cmax and AUCτ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids
(CYP450 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Contraindicated
Cyclosporine*
(CYP3A4 Inhibition)
AUCτ Significantly Increased; No Significant Effect on Cmax When initiating therapy with voriconazole in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When voriconazole is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
Methadone***
(CYP3A4 Inhibition)
Increased Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl
(CYP3A4 Inhibition)
Increased Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see DRUG INTERACTIONS (7)]
Alfentanil
(CYP3A4 Inhibition)
Significantly Increased Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with voriconazole. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [see DRUG INTERACTIONS (7)].
Oxycodone
(CYP3A4 Inhibition)
Significantly Increased Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see DRUG INTERACTIONS (7)].
NSAIDs**** including ibuprofen and diclofenac (CYP2C9 Inhibition) Increased Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed. [see DRUG INTERACTIONS (7)].
Tacrolimus* (CYP3A4 Inhibition) Significantly Increased When initiating therapy with voriconazole in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazole is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin* (CYP2C9 Inhibition) Significantly Increased Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)** Increased Monitoring for adverse events related to oral contraceptives is recommended during coadministration.
Warfarin* (CYP2C9 Inhibition) Prothrombin Time Significantly Increased Monitor PT or other suitable anticoagulation tests. Adjustment of warfarin dosage may be needed.
Omeprazole* (CYP2C19/3A4 Inhibition) Significantly Increased When initiating therapy with voriconazole in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors (CYP3A4 Inhibition) In Vivo Studies Showed No Significant Effects on Indinavir Exposure No dosage adjustment for indinavir when coadministered with voriconazole tablets
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors
Other NNRTIs***** (CYP3A4 Inhibition) A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to NNRTI
Benzodiazepines (CYP3A4 Inhibition) In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.
HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition) In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition) In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition) Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed.
Everolimus (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Concomitant administration of voriconazole and everolimus is not recommended


Table name:
Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme
Inhibitors
Inducers
CYP2C9 
amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast
aprepitant, bosentan, carbamazepine, phenobarbital, rifampin 
CYP1A2 
acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton
montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking 
CYP3A4 
alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton
armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide 


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir ) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Table II. Clinically Significant Drug Interactions With Theophylline*
Drug Type Of Interaction Effect**
*    Refer to  PRECAUTIONS , Drug Interactions for further information regarding table.
**  Average effect on steady-state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.
Adenosine Theophylline blocks adenosine receptors. Higher doses of adenosine may be required to achieve desired effect.
Alcohol A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours. 30% increase
Allopurinol Decreases theophylline clearance at allopurinol doses ≥600 mg/day. 25% increase
Aminoglutethimide Increases theophylline clearance by induction of microsomal enzyme activity. 25% decrease
Carbamazepine Similar to aminoglutethimide. 30% decrease
Cimetidine Decreases theophylline clearance by inhibiting cytochrome P450 1A2. 70% increase
Ciprofloxacin Similar to cimetidine.  40% increase
Clarithromycin Similar to erythromycin. 25% increase
Diazepam Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram Decreases theophylline clearance by inhibiting hydroxylation and demethylation. 50% increase
Enoxacin Similar to cimetidine.  300% increase
Ephedrine Synergistic CNS effects. Increased frequency of nausea, nervousness, and insomnia.
Erythromycin Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3. 35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown. 30% increase
Flurazepam Similar to diazepam. Similar to diazepam.
Fluvoxamine Similar to cimetidine. Similar to cimetidine.
Halothane Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines. Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-A Decreases theophylline clearance. 100% increase
Isoproterenol (I.V.) Increases theophylline clearance. 20% decrease
Ketamine Pharmacologic May lower theophylline seizure threshold.
Lithium Theophylline increases renal lithium clearance. Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam Similar to diazepam. Similar to diazepam.
Methotrexate (MTX) Decreases theophylline clearance. 20% increase after low dose MTX, higher dose MTX may have a greater effect.
Mexiletine Similar to disulfiram. 80% increase
Midazolam Similar to diazepam. Similar to diazepam.
Moricizine Increases theophylline clearance. 25% decrease
Pancuronium Theophylline may antagonize nondepolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition. Larger dose of pancuronium may be required to achieve neuromuscular blockade.
Pentoxifylline Decreases theophylline clearance. 30% increase
Phenobarbital (PB) Similar to aminoglutethimide. 25% decrease after two weeks of concurrent Phenobarbital.
Phenytoin Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption. Serum theophylline and phenytoin concentrations decrease about 40%.
Propafenone Decreases theophylline clearance and pharmacologic interaction. 40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Propranolol Similar to cimetidine and pharmacologic interaction. 100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Rifampin Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity. 20 - 40% decrease
Sulfinpyrazone Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline. 20% decrease
Tacrine Similar to cimetidine, also increases renal clearance of theophylline. 90% increase
Thiabendazole Decreases theophylline clearance. 190% increase
Ticlopidine Decreases theophylline clearance. 60% increase
Troleandomycin Similar to erythromycin. 33 - 100% increase depending on troleandomycin dose.
Verapamil Similar to disulfiram. 20% increase


Table name:
Table 1: Oral drugs that can be administered concomitantly with Auryxia
Amlodipine
Aspirin
Atorvastatin
Calcitriol
Clopidogrel
Digoxin
Diltiazem
Doxercalciferol
Enalapril
Fluvastatin
Glimepiride
Levofloxacin
Losartan
Metoprolol
Pravastatin
Propranolol
Sitagliptin
Warfarin
Oral drugs that have to be separated from Auryxia and meals
Dosing Recommendations
Doxycycline Take at least 1 hour before Auryxia
Ciprofloxacin Take at least 2 hours before or after Auryxia


Table name:
Drugs That Interfere with Hemostasis
  Clinical Impact: Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of celecoxib capsules with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ see Warnings and Precautions (5.11) ].
Aspirin
   Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ see Warnings and Precautions (5.2) ]. In two studies in healthy volunteers, and in patients with osteoarthritis and established heart disease respectively, celecoxib (200-400 mg daily) has demonstrated a lack of interference with the cardioprotective antiplatelet effect of aspirin (100-325 mg).
Intervention: Concomitant use of celecoxib capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions (5.11) ]. Celecoxib capsules is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
  Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
   Intervention: During concomitant use of celecoxib capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of celecoxib capsules and ACE-inhibitors or ARBs in patients who are elderly, volume- depleted, or have impaired renal function, monitor for signs of worsening renal function [ see Warnings and Precautions (5.6) ]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of celecoxib capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ see Warnings and Precautions (5.6) ].
Digoxin
Clinical Impact: The concomitant use of celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of celecoxib capsules and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of celecoxib capsules and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Celecoxib capsules have no effect on methotrexate pharmacokinetics.
Intervention: During concomitant use of celecoxib capsules and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of celecoxib capsules and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of celecoxib capsules and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ see Warnings and Precautions (5.2) ].
Intervention: The concomitant use of celecoxib with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of celecoxib capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of celecoxib capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.
NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.
In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
CYP2C9 Inhibitors or inducers
Clinical Impact: Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Co­-administration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of celecoxib.
Intervention Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers. [ see Clinical Pharmacology (12.3) ].
CYP2D6 substrates
Clinical Impact: In vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6 (e.g. atomoxetine), and celecoxib may enhance the exposure and toxicity of these drugs.
Intervention Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2D6 substrates. [ see Clinical Pharmacology (12.3) ].
Corticosteroids
Clinical Impact: Concomitant use of corticosteroids with celecoxib capsules may increase the risk of GI ulceration or bleeding.
Intervention Monitor patients with concomitant use of celecoxib capsules with corticosteroids for signs of bleeding [see Warnings and Precautions (5.2)].


Table name:
Table 5. Established Drug Interactions Based on Drug Interaction Trials
Concomitant Drug Class:
Drug Name
Effect on Concentration Clinical Comments
ANGIOTENSIN RECEPTOR BLOCKERS
valsartan*
losartan*
candesartan*
↑ angiotensin receptor blockers Decrease the dose of the angiotensin receptor blockers and monitor patients for signs and symptoms of hypotension and/or worsening renal function. If such events occur, consider further dose reduction of the angiotensin receptor blocker or switching to an alternative to the angiotensin receptor blocker.
ANTIARRHYTHMICS
amiodarone*,
bepridil*,
disopyramide*,
flecainide*,
lidocaine (systemic)*,
mexiletine*,
propafenone*,
quinidine*
↑ antiarrhythmics Contraindicated antiarrhythmics [see Contraindications (4)].

Therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with VIEKIRA XR.
ANTIDIABETIC DRUGS
metformin ↔ metformin Monitor for signs of onset of lactic acidosis such as respiratory distress, somnolence, and non-specific abdominal distress or worsening renal function. Concomitant metformin use in patients with renal insufficiency or hepatic impairment is not recommended. Refer to the prescribing information of metformin for further guidance.
ANTIFUNGALS
ketoconazole ↑ ketoconazole When VIEKIRA XR is co-administered with ketoconazole, the maximum daily dose of ketoconazole should be limited to 200 mg per day.
voriconazole* ↓ voriconazole Co-administration of VIEKIRA XR with voriconazole is not recommended unless an assessment of the benefit-to-risk ratio justifies the use of voriconazole.
ANTIPSYCHOTIC
quetiapine* ↑ quetiapine Contraindicated antipsychotics [see Contraindications (4)].

Quetiapine: Initiation of VIEKIRA XR in patients taking quetiapine: Consider alternative anti-HCV therapy to avoid increases in quetiapine exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6th of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for the recommendations on adverse reaction monitoring. Initiation of quetiapine in patients taking VIEKIRA XR: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.
CALCIUM CHANNEL BLOCKERS
amlodipine
nifedipine*
diltiazem*
verapamil*
↑ calcium channel blockers Decrease the dose of the calcium channel blocker. The dose of amlodipine should be decreased by at least 50%.  Clinical monitoring of patients is recommended for edema and/or signs and symptoms of hypotension. If such events occur, consider further dose reduction of the calcium channel blocker or switching to an alternative to the calcium channel blocker.
CORTICOSTEROIDS (INHALED/NASAL)
fluticasone* ↑ fluticasone Concomitant use of VIEKIRA XR with inhaled or nasal fluticasone may reduce serum cortisol concentrations. Alternative corticosteroids should be considered, particularly for long term use.
DIURETICS
furosemide ↑ furosemide (Cmax) Clinical monitoring of patients is recommended and therapy should be individualized based on patient’s response.
ANTIRETROVIRAL AGENTS: PROTEASE INHIBITORS
atazanavir/ritonavir
once daily
↑ paritaprevir When coadministered with VIEKIRA XR, atazanavir 300 mg (without ritonavir) should only be given in the morning.
darunavir/ritonavir ↓ darunavir (Ctrough) Treatment naïve patients or treatment experienced patients with no darunavir associated substitutions:

Darunavir 800 mg once daily (without ritonavir) can be co-administered with VIEKIRA XR.

Treatment experienced patients with at least one darunavir resistance associated substitution or with no baseline resistance information:

Co-administration of darunavir/ritonavir 600/100 mg twice daily with VIEKIRA XR is not recommended.
lopinavir/ritonavir ↑ paritaprevir Co-administration of VIEKIRA XR with lopinavir/ritonavir is not recommended.
ANTIRETROVIRAL AGENTS: NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS
rilpivirine ↑ rilpivirine Contraindicated non-nucleoside reverse transcriptase inhibitors [see Contraindications (4)].

Rilpivirine:
Co-administration of VIEKIRA XR with rilpivirine once daily is not recommended due to potential for QT interval prolongation with higher concentrations of rilpivirine.
HMG CoA REDUCTASE INHIBITORS:
pravastatin
rosuvastatin
↑ pravastatin
↑ rosuvastatin
Contraindicated HMG CoA Reductase Inhibitors [see Contraindications (4)].

Rosuvastatin:
Dose of rosuvastatin should not exceed 10 mg per day.

Pravastatin:
Dose of pravastatin should not exceed 40 mg per day.
IMMUNOSUPPRESSANTS
cyclosporine ↑ cyclosporine For contraindicated immunosuppressants [see Contraindications (4)].

When initiating therapy with VIEKIRA XR, reduce cyclosporine dose to 1/5th of the patient’s current cyclosporine dose. Measure cyclosporine blood concentrations to determine subsequent dose modifications. Upon completion of VIEKIRA XR therapy, the appropriate time to resume pre-VIEKIRA XR dose of cyclosporine should be guided by assessment of cyclosporine blood concentrations. Frequent assessment of renal function and cyclosporine-related side effects is recommended.
LONG ACTING BETA-ADRENOCEPTOR AGONIST
salmeterol* ↑ salmeterol Concurrent administration of VIEKIRA XR and salmeterol is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
MUSCLE RELAXANTS
carisoprodol ↓ carisoprodol
↔ mepobramate
(metabolite of
carisoprodol)
Increase dose if clinically indicated.
cyclobenzaprine ↓cyclobenzaprine
↓norcyclobenzaprine
(metabolite of
cyclobenzaprine)
Increase dose if clinically indicated.
NARCOTIC ANALGESICS
acetaminophen/hydrocodone ↑ hydrocodone
↔ acetaminophen
Reduce the dose of hydrocodone by 50% and monitor patients for respiratory depression and sedation at frequent intervals. Upon completion of VIEKIRA XR therapy, adjust the hydrocodone dose and monitor for signs of opioid withdrawal.
buprenorphine/naloxone ↑ buprenorphine
↑ norbuprenorphine
(metabolite of
buprenorphine)
Patients should be closely monitored for sedation and cognitive effects.
PROTON PUMP INHIBITORS
omeprazole ↓ omeprazole Monitor patients for decreased efficacy of omeprazole. Consider increasing the omeprazole dose in patients whose symptoms are not well controlled; avoid use of more than 40 mg per day of omeprazole.
SEDATIVES/HYPNOTICS
alprazolam ↑ alprazolam Contraindicated Sedatives/Hypnotics [see Contraindications (4)].

Alprazolam:
Clinical monitoring of patients is recommended. A decrease in alprazolam dose can be considered based on clinical response.
diazepam ↓ diazepam
↓ nordiazepam
(metabolite of
diazepam)
Increase dose if clinically indicated.
See Clinical Pharmacology, Tables 7 and 8 .
The direction of the arrow indicates the direction of the change in exposures (Cmax and AUC) (↑ = increase of more than 20%, ↓ = decrease of more than 20%, ↔ = no change or change less than 20%).
*not studied.


Table name:
 Antiretrovirals
Clinical Impact:   The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known.
• Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology (12.3)].
• Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see Clinical Pharmacology (12.3)].
• There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole.
Intervention:   Rilpivirine-containing products: Concomitant use with omeprazole is contraindicated [see Contraindications (4)].
Atazanavir: Avoid concomitant use with omeprazole. See prescribing information for atazanavir for dosing information.
Nelfinavir: Avoid concomitant use with omeprazole. See prescribing information for nelfinavir.
Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities.
Other antiretrovirals: See prescribing information for specific antiretroviral drugs.
 Warfarin
Clinical Impact:   Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.  
Intervention:   Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range.  
 Methotrexate
Clinical Impact:   Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions (5.11)].
Intervention:   A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate.
 CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam)
 Clopidogrel
Clinical Impact:   Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology (12.3)].
There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel.
Intervention:   Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy [see Warnings and Precautions (5.6)].
Citalopram
Clinical Impact: Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology (12.3)].
Intervention:   Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.
Cilostazol
Clinical Impact: Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology (12.3)].
Intervention:   Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.
Phenytoin
Clinical Impact: Potential for increased exposure of phenytoin.
Intervention:   Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin.
Diazepam
Clinical Impact:   Increased exposure of diazepam [see Clinical Pharmacology (12.3)].
Intervention:   Monitor patients for increased sedation and reduce the dose of diazepam as needed.
Digoxin
Clinical Impact:   Potential for increased exposure of digoxin [see Clinical Pharmacology (12.3)].
Intervention:   Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information.  
 Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)
Clinical Impact:   Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
Intervention:   Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF [see Clinical Pharmacology (12.3)]. See the prescribing information for other drugs dependent on gastric pH for absorption.
 Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact:   Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions.
Intervention:   See Contraindications, Warnings and Precautions in prescribing information for clarithromycin. See Drug Interactions in prescribing information for amoxicillin.
 Tacrolimus
Clinical Impact:   Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.
Intervention:   Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
 Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact:   Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions (5.10),Clinical Pharmacology (12.2)].
Intervention:   Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
Interaction with Secretin Stimulation Test  
Clinical Impact:   Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention:   Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology (12.2)].
False Positive Urine Tests for THC
Clinical Impact:   There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.
Intervention:   An alternative confirmatory method should be considered to verify positive results.
Other
Clinical Impact:   There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram).
Intervention:   Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole.


Table name:
AED Coadministered AED Concentration Topiramate Concentration
Phenytoin NC or 25% increasea 48% decrease
Carbamazepine (CBZ) NC 40% decrease
CBZ epoxideb NC NE
Valproic acid 11% decrease 14% decrease
Phenobarbital NC NE
Primidone NC NE
Lamotrigine NC at TPM doses up to 400 mg/day 13% decrease


Table name:
Figure 1: Effect of interacting drugs on the pharmacokinetics of venlafaxine and active metabolite O-desmethylvenlafaxine (ODV). Abbreviations: ODV, O-desmethylvenlafaxine; AUC, area under the curve; Cmax, peak plasma concentrations; EM's, extensive metabolizers; PM's, poor metabolizers * No dose adjustment on co-administration with CYP2D6 inhibitors (Fig 3 and Metabolism Section 12.3)


Table name:
Interacting Agents Prescribing Recommendations
Itraconazole, ketoconazole, Posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine,danazol Contraindicated with simvastatin 
Verapamil, diltiazem Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine  Do not exceed 20 mg simvastatin daily
Grapefruit juice Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T 4 and T 3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin/Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens/Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non-Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT 4 . Continued administration results in a decrease in serum T 4 and normal FT 4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T 4 and T 3 to TBG and transthyretin. An initial increase in serum FT 4 is followed by return of FT 4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T 4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T 4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ³ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T 4 to T 3, leading to decreased T 3 levels. However, serum T 4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T 3 and T 4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T 3 concentrations by 30% with minimal change in serum T 4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T 3 and T 4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias
and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123 I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Effects on steady-state fexofenadine pharmacokinetics after 7 days of co-administration with fexofenadine hydrochloride 120 mg every 12 hours (two times the recommended twice daily dose) in healthy volunteers (n=24)
Concomitant Drug CmaxSS
(Peak plasma concentration)
AUCss(0–12h)
(Extent of systemic exposure)
Erythromycin
(500 mg every 8 hrs)
+82% +109%
Ketoconazole
(400 mg once daily)
+135% +164%


Table name:

a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
b = Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated
AED Co-administered 
AED Concentration
Topiramate Concentration
Phenytoin 
NC or 25% increasea
48% decrease
Carbamazepine (CBZ)
NC 
40% decrease
CBZ epoxideb
NC
NE
Valproic acid 
11% decrease
14% decrease
Phenobarbital
NC
NE
Primidone 
NC
NE
Lamotrigine 
NC at TPM doses up to 400 mg/day
13% decrease


Table name:
Table II. Clinically significant drug interactions with theophylline*.
* Refer to PRECAUTIONS, Drug Interactions for further information regarding table.
** Average effect on steady state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.
DrugType of InteractionEffect**
AdenosineTheophylline blocks adenosine receptors.Higher doses of adenosine may be required to achieve desired effect.
AlcoholA single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours.30% increase
AllopurinolDecreases theophylline clearance at allopurinol doses ≥600 mg/day.25% increase
AminoglutethimideIncreases theophylline clearance by induction of microsomal enzyme activity.25% decrease
CarbamazepineSimilar to aminoglutethimide.30% decrease
CimetidineDecreases theophylline clearance by inhibiting cytochrome P450 1A2.70% increase
CiprofloxacinSimilar to cimetidine.40% increase
ClarithromycinSimilar to erythromycin.25% increase
DiazepamBenzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors.Larger diazepam doses may be required to produce desired level of sedation.
Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
DisulfiramDecreases theophylline clearance by inhibiting hydroxylation and demethylation.50% increase
EnoxacinSimilar to cimetidine.300% increase
EphedrineSynergistic CNS effects.Increased frequency of nausea, nervousness, and insomnia.
ErythromycinErythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3.35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
EstrogenEstrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown.30% increase
FlurazepamSimilar to diazepam.Similar to diazepam.
FluvoxamineSimilar to cimetidine.Similar to cimetidine.
HalothaneHalothane sensitizes the myocardium. to catecholamines, theophylline increases release of endogenous catecholamines.Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-ADecreases theophylline clearance.100% increase
Isoproterenol (IV)Increases theophylline clearance.20% decrease
KetaminePharmacologic seizure threshold.May lower theophylline
LithiumTheophylline increases renal lithium clearance.Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
LorazepamSimilar to diazepam.Similar to diazepam.
Methotrexate (MTX)Decreases theophylline clearance.20% increase after low dose MTX, higher dose MTX may have a greater effect.
MexiletineSimilar to disulfiram.80% increase
MidazolamSimilar to diazepam.Similar to diazepam.
MoricizineIncreases theophylline clearance.25% decrease
PancuroniumTheophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition.Larger dose of pancuronium may be required to achieve neuromuscular blockade.
PentoxifyllineDecreases theophylline clearance.30% increase
Phenobarbital (PB)Similar to aminoglutethimide.25% decrease after two weeks of concurrent PB.
PhenytoinPhenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption.Serum theophylline and phenytoin concentrations decrease about 40%.
PropafenoneDecreases theophylline clearance and pharmacologic interaction.40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
PropranololSimilar to cimetidine and pharmacologic interaction.100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
RifampinIncreases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity.20-40% decrease
SulfinpyrazoneIncreases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline.20% decrease
TacrineSimilar to cimetidine, also increases renal clearance of theophylline.90% increase
ThiabendazoleDecreases theophylline clearance.190% increase
TiclopidineDecreases theophylline clearance.60% increase
TroleandomycinSimilar to erythromycin.33-100% increase depending on troleandomycin dose.
VerapamilSimilar to disulfiram.20% increase


Table name:
Table 12: Clinically Important Drug Interactions with SAPHRIS
Concomitant Drug Name or Drug Class Clinical Rationale Clinical Recommendation
Antihypertensive Drugs
Because of its α1-adrenergic antagonism with potential for inducing hypotension, SAPHRIS may enhance the effects of certain antihypertensive agents [see Warnings and Precautions (5.7)]. Monitor blood pressure and adjust dosage of antihypertensive drug accordingly.
Strong CYP1A2 Inhibitors (e.g., Fluvoxamine) SAPHRIS is metabolized by CYP1A2. Marginal increase of asenapine exposure was observed when SAPHRIS is used with fluvoxamine at 25 mg administered twice daily [see Clinical Pharmacology (12.3)]. However, the tested fluvoxamine dose was suboptimal. Full therapeutic dose of fluvoxamine is expected to cause a greater increase in asenapine exposure. Dosage reduction for SAPHRIS based on clinical response may be necessary.
CYP2D6 substrates and inhibitors (e.g., paroxetine) SAPHRIS may enhance the inhibitory effects of paroxetine on its own metabolism. Concomitant use of paroxetine with SAPHRIS increased the paroxetine exposure by 2-fold as compared to use paroxetine alone [see Clinical Pharmacology (12.3)]. Reduce paroxetine dose by half when paroxetine is used in combination with SAPHRIS.


Table name:
Factors
Dosage Adjustment for Aripiprazole tablets
Known CYP2D6 Poor Metabolizers
Administer half of usual dose
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors
Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors
Administer half of usual dose
Strong CYP2D6 and CYP3A4 inhibitors
Administer a quarter of usual dose
Strong CYP3A4 inducers
Double usual dose over 1 to 2 weeks


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T 4 and T 3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin/Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens/Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non-Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT 4 . Continued administration results in a decrease in serum T 4 and normal FT 4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T 4 and T 3 to TBG and transthyretin. An initial increase in serum FT 4 is followed by return of FT 4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T 4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T 4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ³ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T 4 to T 3, leading to decreased T 3 levels. However, serum T 4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T 3 and T 4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T 3 concentrations by 30% with minimal change in serum T 4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T 3 and T 4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias
and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123 I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Drug Interactions Associated with Increased Risk of  Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice Avoid grapefruit juice


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T 4 and T 3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT 4. Continued administration results in a decrease in serum T 4 and normal FT 4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T 4 and T 3 to TBG and transthyretin. An initial increase in serum FT 4, is followed by return of FT 4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T 4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T 4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T 4 to T 3, leading to decreased T 3 levels. However, serum T 4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T 3 and T 4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T 3 concentrations by 30% with minimal change in serum T 4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T 3 and T 4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 3: Clinically Relevant Interactions Affecting Naldemedine When Co-Administered with Other Drugs
Strong CYP3A Inducers (e.g., rifampin, carbamazepine, phenytoin, St. John’s Wort)
Clinical Impact Significant decrease in plasma naldemedine concentrations, which may reduce efficacy [see Clinical Pharmacology (12.3)]
Intervention Avoid use of SYMPROIC with strong CYP3A inducers.
Other Opioid Antagonists
Clinical Impact Potential for additive effect of opioid receptor antagonism and increased risk of opioid withdrawal.
Intervention Avoid use of SYMPROIC with another opioid antagonist.
Moderate (e.g., fluconazole, atazanavir, aprepitant, diltiazem, erythromycin) and Strong (e.g., itraconazole, ketoconazole, clarithromycin, ritonavir, saquinavir) CYP3A Inhibitors
Clinical Impact Increase in plasma naldemedine concentrations [see Clinical Pharmacology (12.3)]
Intervention Monitor for potential naldemedine-related adverse reactions [see Adverse Reactions (6.1)].
P-glycoprotein (P-gp) Inhibitors (e.g., amiodarone, captopril, cyclosporine, quercetin, quinidine, verapamil)
Clinical Impact Increase in plasma naldemedine concentrations [see Clinical Pharmacology (12.3)]
Intervention Monitor for potential naldemedine-related adverse reactions [see Adverse Reactions (6.1)].


Table name:
Interacting Drug Interaction
Theophylline Serious and fatal reactions. Avoid concomitant use. Monitor serum level ( 7)
Warfarin Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding ( 7)
Antidiabetic agents Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose ( 7)
Phenytoin Monitor phenytoin level ( 7)
Methotrexate Monitor for methotrexate toxicity ( 7)
Cyclosporine May increase serum creatinine. Monitor serum creatinine ( 7)
Multivalent cation-containing products including antacids, metal cations, or didanosine Decreased Ciprofloxacin absorption. Take 2 hours before or 6 hours after Ciprofloxacin ( 7)


Table name:
Summary of AED interactions with topiramate (7.1).
AED Co-administered AED Concentration Topiramate Concentration
Phenytoin NC or 25% increasea 48% decrease
Carbamazepine (CBZ) NC 40% decrease
CBZ epoxideb NC NE
Valproic acid 11% decrease 14% decrease
Phenobarbital NC NE
Primidone NC NE
Lamotrigine NC at TPM doses up to 400mg/day 13% decrease


Table name:
Bleeding times
Clinical Impact: Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention: This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact: The administration of naproxen may result in increased urinary values for 17 ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention: Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact: Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention: This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4 , 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.11 , 7.3)


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Factors Dosage Adjustments for Aripiprazole
Known CYP2D6 Poor Metabolizers Administer half of usual dose
Known CYP2D6 Poor Metabolizersand strong CYP3A4 inhibitors Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors Administer half of usual dose
Strong CYP2D6 and CYP3A4inhibitors Administer a quarter of usual dose
Strong CYP3A4 inducers Double usual dose over 1 to 2 weeks


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine Decreased lamotrigine concentrations approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? carbamazepine epoxide May increase carbamazepine epoxide levels.
Lopinavir/ritonavir ↓ lamotrigine Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir ↓ lamotrigine Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine Increased lamotrigine concentrations slightly more than 2 fold.
? valproate There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.


Table name:
Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) VIAGRA 50 mg (95% CI)
Supine 9.08 (5.48, 12.68)
Standing

11.62 (7.34, 15.90)



Table name:
Table 4: Clinically Relevant Interactions Affecting Omeprazole When Co-Administered with Other Drugs
CYP2C19 or CYP3A4 Inducers
Clinical Impact:
Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology (12.3)].
Intervention:
St. John’s Wort, rifampin: Avoid concomitant use with omeprazole [see Warnings and Precautions (5.9)].
Ritonavir-containing products: see prescribing information for specific drugs.
CYP2C19 or CYP3A4 Inhibitors
Clinical Impact:
Increased exposure of omeprazole [see Clinical Pharmacology (12.3)].
Intervention:
Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered.
 
See prescribing information for voriconazole.


Table name:
Table 8: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s) Recommendation Comments
Tizanidine Contraindicated Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2) ]
Theophylline Avoid Use
(Plasma Exposure Likely to be Increased and Prolonged)
Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions (5.9) ].
Drugs Known to Prolong QT Interval Avoid Use Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.11) and Use in Specific Populations (8.5) ].
Oral antidiabetic drugs Use with caution
Glucose-lowering effect
potentiated
Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly
sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs [see Adverse Reactions (6.1) ].
Phenytoin Use with caution
Altered serum levels of phenytoin (increased and decreased)
To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin with phenytoin.
Cyclosporine Use with caution
(transient elevations in serum creatinine)
Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs Use with caution
(Increase in anticoagulant effect)
The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anticoagulant (for example, warfarin).
Methotrexate Use with caution
Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels
Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole Use with caution Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin [see Warnings and Precautions (5.15) ].
Clozapine Use with caution Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs Use with caution Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil Use with caution
Two-fold increase in exposure
Monitor for sildenafil toxicity [see Clinical Pharmacology (12.3) ].
Duloxetine Avoid Use
Five-fold increase in duloxetine exposure
If unavoidable, monitor for duloxetine toxicity.
Caffeine/Xanthine Derivatives Use with caution
Reduced clearance resulting in elevated levels and prolongation of serum half-life
Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Probenecid Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels) Potentiation of ciprofloxacin toxicity may occur.


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine / Dopamine Agonists Glucocorticoids Octreotide Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( > 1 µg/kg/min); Glucocorticoids (hydrocortisone > 100 mg/day or equivalent); Octreotide ( > 100 µg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T 4 and T 3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) Administration of these agents with levothyroxine results in an initial transient increase in FT 4. Continued administration results in a decrease in serum T 4 and normal FT 4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T 4 and T 3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT 4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T 4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T 4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5’-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone > 4 mg/day) Propylthiouracil (PTU) Administration of these enzyme inhibitors decreases the peripheral conversion of T 4 to T 3, leading to decreased T 3 levels. However, serum T 4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T 3 and T 4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T 3 concentrations by 30% with minimal change in serum T 4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T 3 and T 4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Growth Hormones - Somatrem - Somatropin Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline) Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.


Table name:
Table 5. Established Drug Interactions Based on Drug Interaction Trials
Concomitant Drug Class: Drug Name Effect on Concentration Clinical Comments
ANGIOTENSIN RECEPTOR BLOCKERS e.g.
valsartan*,
losartan*,
candesartan*
↑ angiotensin receptor blockers Decrease the dose of the angiotensin receptor blockers and monitor patients for signs and symptoms of hypotension and/or worsening renal function. If such events occur, consider further dose reduction of the angiotensin receptor blocker or switching to an alternative to the angiotensin receptor blocker.
ANTIARRHYTHMICS
digoxin ↑ digoxin For contraindicated antiarrhythmics [see Contraindications (4)].

Decrease digoxin dose by 30-50%. Appropriate monitoring of serum digoxin levels is recommended.
amiodarone*,
bepridil*,
disopyramide*,
flecainide*,
lidocaine (systemic)*,
mexiletine*,
propafenone*,
quinidine*
↑ antiarrhythmics Therapeutic monitoring (if available) is recommended for antiarrhythmics when co-administered with TECHNIVIE.
ANTIDIABETIC DRUGS
metformin ↔ metformin Monitor for signs of onset of lactic acidosis such as respiratory distress, somnolence, and non-specific abdominal distress or worsening renal function. Concomitant metformin use in patients with renal insufficiency or hepatic impairment is not recommended. Refer to the prescribing information of metformin for further guidance.
ANTIFUNGALS
ketoconazole ↑ ketoconazole When TECHNIVIE is co-administered with ketoconazole, the maximum daily dose of ketoconazole should be limited to 200 mg per day.
voriconazole* ↓ voriconazole Co-administration of TECHNIVIE with voriconazole is not recommended unless an assessment of the benefit-to-risk ratio justifies the use of voriconazole.
ANTIPSYCHOTICS
quetiapine* ↑ quetiapine For contraindicated antipsychotics [see Contraindications (4)].

Initiation of TECHNIVIE in patients taking quetiapine: Consider alternative anti-HCV therapy to avoid increases in quetiapine exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6th of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring. Initiation of quetiapine in patients taking TECHNIVIE: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.
CALCIUM CHANNEL BLOCKERS
amlodipine,
nifedipine*,
diltiazem*,
verapamil*
↑ calcium channel blockers Decrease the dose of the calcium channel blocker. The dose of amlodipine should be decreased by at least 50%. Clinical monitoring of patients is recommended for edema and/or signs and symptoms of hypotension. If such events occur, consider further dose reduction of the calcium channel blocker or switching to an alternative to the calcium channel blocker.
CORTICOSTEROIDS (INHALED/NASAL)
fluticasone* ↑ fluticasone Concomitant use of TECHNIVIE with inhaled or nasal fluticasone may reduce serum cortisol concentrations. Alternative corticosteroids should be considered, particularly for long term use.
DIURETICS
furosemide ↑ furosemide (Cmax) Clinical monitoring of patients is recommended and therapy should be individualized based on patient’s response.
HIV-ANTIVIRAL AGENTS
atazanavir or atazanavir/ritonavir ↑ paritaprevir Co-administration of TECHNIVIE with atazanavir or atazanavir/ritonavir is not recommended.
darunavir/ritonavir ↓ darunavir (Ctrough) Treatment naïve patients or treatment experienced patients with no darunavir-associated mutations:

Darunavir 800 mg once daily (without ritonavir) can be co-administered with TECHNIVIE.
lopinavir/ritonavir ↑ paritaprevir Co-administration of TECHNIVIE with lopinavir/ritonavir is not recommended.
rilpivirine ↑ rilpivirine For contraindicated non-nucleoside reverse transcriptase inhibitors [see Contraindications (4)].

Co-administration of TECHNIVIE with rilpivirine once daily is not recommended due to potential for QT interval prolongation with higher concentrations of rilpivirine.
HMG CoA REDUCTASE INHIBITORS
pravastatin ↑ pravastatin For contraindicated HMG CoA Reductase Inhibitors [see Contraindications (4)].

When TECHNIVIE is co-administered with pravastatin, the dose of pravastatin should not exceed 40 mg per day.
IMMUNOSUPPRESSANTS
cyclosporine ↑ cyclosporine For contraindicated immunosuppressants [see Contraindications (4)].

When initiating therapy with TECHNIVIE, reduce cyclosporine dose to 1/5th of the patient’s current cyclosporine dose. Measure cyclosporine blood concentrations to determine subsequent dose modifications. Upon completion of TECHNIVIE therapy, the appropriate time to resume pre-TECHNIVIE dose of cyclosporine should be guided by assessment of cyclosporine blood concentrations. Frequent assessment of renal function and cyclosporine-related side effects is recommended.
LONG ACTING BETA-ADRENOCEPTOR AGONIST
salmeterol* ↑ salmeterol Concurrent administration of TECHNIVIE and salmeterol is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
MUSCLE RELAXANTS
carisoprodol ↓ carisoprodol
↔ mepobramate
(metabolite of carisoprodol)
Increase dose if clinically indicated.
cyclobenzaprine ↓cyclobenzaprine
↓norcyclobenzaprine (metabolite of cyclobenzaprine)
Increase dose if clinically indicated.
NARCOTIC ANALGESICS
buprenorphine/naloxone ↑ buprenorphine
↑ norbuprenorphine
(metabolite of buprenorphine)
Patients should be closely monitored for sedation and cognitive effects.
Hydrocodone/
acetaminophen
↑ hydrocodone
↔ acetaminophen
Reduce the dose of hydrocodone by 50% and monitor patients for respiratory depression and sedation at frequent intervals. Upon completion of TECHNIVIE therapy, adjust the hydrocodone dose and monitor for signs of opioid withdrawal.
PROTON PUMP INHIBITORS
omeprazole ↓ omeprazole Monitor patients for decreased efficacy of omeprazole. Consider increasing the omeprazole dose in patients whose symptoms are not well controlled; avoid use of more than 40 mg per day of omeprazole.
SEDATIVES/HYPNOTICS
alprazolam ↑ alprazolam For contraindicated Sedatives/Hypnotics [see Contraindications (4)].

Clinical monitoring of patients is recommended. A decrease in alprazolam dose can be considered based on clinical response.
diazepam ↓ diazepam
↓ nordiazepam (metabolite of diazepam)
Increase dose if clinically indicated.
*Not studied.
See Clinical Pharmacology, Tables 7 and 8 .
The direction of the arrow indicates the direction of the change in exposures (Cmax and AUC) (↑ = increase of more than 20%, ↓ = decrease of more than 20%).


Table name:
Table 4 Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table 5 for Magnitude of Interaction.
Drug Name Effect on Concentration of
Nevirapine or Concomitant Drug
Clinical Comment
HIV Antiviral Agents: Protease Inhibitors (PIs)
Atazanavir/RitonavirThe interaction between Nevirapine and the drug was evaluated in a clinical study. All other drug interactions shown are predicted. ↓ Atazanavir
↑ Nevirapine
Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures.
Fosamprenavir
↓ Amprenavir
↑ Nevirapine
Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.
Fosamprenavir/Ritonavir
↓ Amprenavir

↑ Nevirapine
No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied.
Indinavir
↓ Indinavir
The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established.
Lopinavir/Ritonavir ↓Lopinavir
Dosing in adult patients:

A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.

Dosing in pediatric patients:

Please refer to the Kaletra® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.
Nelfinavir
↓Nelfinavir M8 Metabolite
↓Nelfinavir Cmin
The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established.
Saquinavir/ritonavir
The interaction between nevirapine and saquinavir/ritonavir has not been evaluated
The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz
↓ Efavirenz
The appropriate doses of these combinations with respect to safety and efficacy have not been established.
Delavirdine
Etravirine
Rilpivirine
Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial.
Hepatitis C Antiviral Agents
Boceprevir
Plasma concentrations of boceprevir may be decreased due to induction of CYP3A4/5 by nevirapine.
Nevirapine and boceprevir should not be coadministered because decreases in boceprevir plasma concentrations may result in a reduction in efficacy.
Telaprevir
Plasma concentrations of
telaprevir may be decreased
due to induction of CYP3A4
by nevirapine and plasma
concentrations of nevirapine
may be increased due to
inhibition of CYP3A4
by telaprevir.
Nevirapine and telaprevir should not be coadministered because changes in plasma concentrations of nevirapine, telaprevir, or both may result in a reduction in telaprevir efficacy or an increase in nevirapine-associated adverse events.
Other Agents
Analgesics:
Methadone
↓ Methadone
Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Antiarrhythmics:
Amiodarone, disopyramide, lidocaine
Plasma concentrations may be decreased.
Appropriate doses for this combination have not been established.
Antibiotics:
Clarithromycin
↓ Clarithromycin
↑ 14-OH clarithromycin
Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.
Antibiotics:
Rifabutin
↑ Rifabutin
Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.
Rifampin
↓ Nevirapine
Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Anticonvulsants:
Carbamazepine, clonazepam, ethosuximide

Plasma concentrations of nevirapine and the
anticonvulsant may
be decreased.

Use with caution and monitor virologic response and levels of anticonvulsants.
Antifungals:
Fluconazole
↑Nevirapine
Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events.
Ketoconazole
↓ Ketoconazole
Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.
Itraconazole
↓ Itraconazole
Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug.
Antithrombotics:
Warfarin

Plasma concentrations may be increase.

Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.
Calcium channel blockers:
Diltiazem, nifedipine, verapamil

Plasma concentrations may be decreased.

Appropriate doses for these combinations have not been established.
Cancer chemotherapy:
Cyclophosphamide

Plasma concentrations may be decreased.

Appropriate doses for this combination have not been established.
Ergot alkaloids:
Ergotamine

Plasma concentrations may be decreased.

Appropriate doses for this combination have not been established.
Immunosuppressants:
Cyclosporine, tacrolimus, sirolimus

Plasma concentrations may be decreased.

Appropriate doses for these combinations have not been established.
Motility agents:
Cisapride

Plasma concentrations may be decreased.

Appropriate doses for this combinations have not been established.
Opiate agonists:
Fentanyl

Plasma concentrations may be decreased.

Appropriate doses for this combinations have not been established.
Oral contraceptives:
Ethinyl estradiol and Norethindrone
↓ Ethinyl estradiol
↓ Norethindrone
Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended.


Table name:
NA – Not available/reported
Digoxin concentrations increased greater than 50%
   Digoxin Serum   
Concentration Increase
   Digoxin AUC   
Increase
Recommendations
Amiodarone 70% NA Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring.
Captopril 58% 39%
Clarithromycin NA 70%
Dronedarone NA 150%
Gentamicin 129-212% NA
Erythromycin 100% NA
Itraconazole 80% NA
Nitrendipine 57% 15%
Propafenone NA 60-270%
Quinidine 100% NA
Ranolazine 50% NA
Ritonavir NA 86%
Tetracycline 100% NA
Verapamil 50-75% NA
Digoxin concentrations increased less than 50%
Atorvastatin 22% 15% Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring.
Carvedilol 16% 14%
Diltiazem 20% NA
Indomethacin 40% NA
Nefazodone 27% 15%
Nifedipine 45% NA
Propantheline 24% 24%
Quinine NA 33%
Saquinavir 27% 49%
Spironolactone      25% NA
Telmisartan 20-49% NA
Tolvaptan 30% NA
Trimethoprim 22-28% NA
Digoxin concentrations increased, but magnitude is unclear
Alprazolam, azithromycin, cyclosporine, diclofenac,
diphenoxylate, epoprostenol, esomeprazole, ibuprofen,
ketoconazole, lansoprazole, metformin, omeprazole,
rabeprazole,
Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin concentrations decreased
Acarbose, activated charcoal, albuterol, antacids, certain
cancer chemotherapy or radiation therapy, cholestyramine,
colestipol, extenatide, kaolin-pectin, meals high in bran,
metoclopramide, miglitol, neomycin, penicillamine,
phenytoin, rifampin, St. John’s Wort, sucralfate,
sulfasalazine
Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20-40% as necessary.
No significant Digoxin exposure changes
Please refer to section 12 for a complete list of drugs which     
were studied but reported no significant changes on digoxin exposure.
No additional actions are required.     


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
 Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)  Avoid atorvastatin
 HIV protease inhibitor (lopinavir plus ritonavir)  Use with caution and lowest dose necessary
 Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir )  Do not exceed 20 mg atorvastatin daily
 HIV protease inhibitor (nelfinavir)  Do not exceed 40 mg atorvastatin daily


Table name:
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice Avoid grapefruit juice


Table name:
Bleeding times
Clinical Impact: Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention: This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact: The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention: Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact: Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention: This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.


Table name:
AED  Co - administered
AED  Concentration
Topiramate  Concentration
Phenytoin
NCor25%increase a
48%decrease
Carbamazepine(CBZ)
NC
40%decrease
CBZepoxide b
NC 
            NE
Valproic acid
11%decrease
14%decrease
Phenobarbital
NC
            NE
Primidone
NC
           NE
Lamotrigine
NCatTPM dosesupto400  mg/day 
         13%decrease


Table name:
Concomitant Drug Name or Drug Class Clinical Rationale Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) The concomitant use of aripiprazole with strong CYP3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)]. With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin) The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)]. With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Antihypertensive Drugs Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.8)].
Benzodiazepines (e.g., lorazepam) The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.8)] Monitor sedation and blood pressure. Adjust dose accordingly.


Table name:
Table 11: Effect of Other Drugs on Voriconazole Pharmacokinetics
Drug/Drug Class
(Mechanism of Interaction by the Drug)
Voriconazole Plasma Exposure
(Cmax and AUCτ after
200 mg Q12h)
Recommendations for Voriconazole
Dosage Adjustment/Comments
RifampinResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg Q12h voriconazole to healthy subjects, and Rifabutin
(CYP450 Induction)
Significantly Reduced Contraindicated
EfavirenzResults based on in vivo clinical study following repeat oral dosing with 400 mg Q12h for 1 day, then 200 mg Q12h for at least 2 days voriconazole to healthy subjects
(CYP450 Induction)
Significantly Reduced When voriconazole is coadministered with efavirenz, voriconazole maintenance dose should be increased to 400 mg Q12h and efavirenz should be decreased to 300 mg Q24h (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION-Dosage Adjustment)
High-dose Ritonavir (400mg Q12h)
(CYP450 Induction)
Significantly Reduced Contraindicated
Low-dose Ritonavir (100mg Q12h)
(CYP450 Induction)
Reduced Coadministration of voriconazole and low-dose ritonavir (100 mg Q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Carbamazepine
(CYP450 Induction)
Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction Contraindicated
Long Acting Barbiturates
(CYP450 Induction)
Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction Contraindicated
Phenytoin
(CYP450 Induction)
Significantly Reduced Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV every 12 hrs or from 200 mg to 400 mg orally every 12 hrs (100 mg to 200 mg orally every 12 hrs in patients weighing less than 40 kg)
St. John's Wort
(CYP450 inducer; P-gp inducer)
Significantly Reduced Contraindicated
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition) Increased Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Other HIV Protease Inhibitors
(CYP3A4 Inhibition)
In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure

In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)
No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir

Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors
(CYP3A4 Inhibition or CYP450 Induction)
In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to voriconazole

A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure)

Careful assessment of voriconazole effectiveness


Table name:
edema hypothyroidism 
hereditary coumarin resistance nephrotic syndrome
hyperlipemia


Table name: Decreased Moxifloxacin Hydrochloride absorption. Take Moxifloxacin Hydrochloride Tablet at least 4 hours before or 8 hours after these products. (2.2, 7.1, 12.3)Anticoagulant effect enhanced. Monitor prothrombin time/INR, and bleeding. (6, 7.2, 12.3)Proarrhythmic effect may be enhanced. Avoid concomitant use. (5.3, 7.4)Carefully monitor blood glucose. (5.10, 7.3)
Interacting Drug Interaction
Multivalent cation-containing products including : antacids, sucralfate, multivitamins
Warfarin
Class IA and Class III antiarrhythmics:
Antidiabetic agents


Table name:
Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death.
Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.4)].
Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may
result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-
   containing radiographic
   contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which
may result in hyperthyroidism
Amiodarone
Iodide (including iodine-
containing Radiographic
contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase Drugs that may decrease
serum TBG concentration serum TBG concentration
Clofibrate Androgens / Anabolic Steroids
Estrogen-containing oral Asparaginase
   contraceptives Glucocorticoids
Estrogens (oral) Slow-Release Nicotinic Acid
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal
Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake
Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
NITROPRUSSIDE
Para-aminosalicylate sodium
Perphenazine
Resorcinol
 (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme
Inhibitors
Inducers
CYP2C9 
amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast
aprepitant, bosentan, carbamazepine, phenobarbital, rifampin 
CYP1A2 
acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton
montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking 
CYP3A4 
alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton
armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide 


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.5, 5.1, 7.1, 7.2, 7.3, 7.4)
Interacting Agents Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone Avoid simvastatin
Gemfibrozil, cyclosporine, danazol Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil Do not exceed 20 mg simvastatin daily
Grapefruit juice Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
 ↓= Decreased (induces lamotrigine gluronidation).
 ↑= Increased (inhibits lamotrigine glucuronidation).
 ?= Conflicting data.
 Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel  ↓ lamotrigine  Decreased lamotrigine levels approximately 50%.
 ↓ levonorgestrel  Decrease in levonorgestrel component by 19%.
 Carbamazepine and carbamazepine epoxide  ↓ lamotrigine  Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
 ? carbamazepine epoxide  May increase carbamazepine epoxide levels.
 Phenobarbital/Primidone  ↓ lamotrigine  Decreased lamotrigine concentration approximately 40%.
 Phenytoin (PHT)  ↓ lamotrigine  Decreased lamotrigine concentration approximately 40%.
 Rifampin  ↓ lamotrigine  Decreased lamotrigine AUC approximately 40%.
 Valproate  ↑ lamotrigine  Increased lamotrigine concentrations slightly more than 2-fold.
   ? valproate  Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
Table 7  Summary of AED Interactions with Trileptal
AED
Coadministered
Dose of AED
(mg/day)
Trileptal Dose
(mg/day)
Influence of
Trileptal on AED
Concentration

(Mean Change,

90% Confidence

Interval)
Influence of
AED on MHD

Concentration

(Mean Change,

90% Confidence

Interval)
Carbamazepine 400-2000 900 nc 1 40% decrease
[CI: 17% decrease,
57% decrease]
Phenobarbital 100-150 600-1800 14% increase
[CI: 2% increase,
24% increase]
25% decrease
[CI: 12% decrease,
51% decrease]
Phenytoin 250-500 600-1800
>1200-2400
nc 1,2
up to 40%
increase 3 
[CI: 12% increase,
60% increase]
30% decrease
[CI: 3% decrease,
48% decrease]
Valproic acid 400-2800 600-1800 nc 1 18% decrease
[CI: 13% decrease,
40% decrease]


Table name:
Antibiotics Antineoplastic   Antifungals           Anti-
Inflammatory
Drugs
Gastrointestinal 
Agents
Immunosuppressives     Other Drugs
ciprofloxacingentamicin tobramycin trimethoprim with sulfamethoxazole vancomycin melphalan amphotericin Bketoconazole azapropazoncolchicine diclofenacnaproxen sulindac cimetidine ranitidine tacrolimus fibric acid
derivatives (e.g., bezafibrate, 
fenofibrate)


Table name:
Table 2: Examples of CYP450 Interactions with Warfarin
  Enzyme   Inhibitors   Inducers
  CYP2C9   amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast   aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
  CYP1A2   acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton   montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
  CYP3A4   alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton   armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Interacting  Agents 
Prescribing  Recommendations 
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, 
posaconazole, voriconazole, erythromycin, clarithromycin, 
telithromycin, HIV protease inhibitors, boceprevir, telaprevir, 
nefazodone, cobicistatcontaining products), gemfibrozil, 
cyclosporine, danazol 
 Contraindicated with simvastatin 
Verapamil, diltiazem, dronedarone
Do not exceed 10 mg simvastatin daily 
Amiodarone, amlodipine, ranolazine
Do not exceed 20 mg simvastatin daily 
Lomitapide
For patients with HoFH, do not exceed 
20 mg simvastatin dailyFor patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice 
Avoid grapefruit juice  


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion–the reduction is not sustained; therefore, hypothyroidism does not occur
  Dopamine / Dopamine Agonists
Glucocorticoids
Octreotide
  Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
  Aminoglutethimide
Amiodarone
Iodide(including iodine-containing
  Radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
  Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients.  The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
  Amiodarone
Iodide(including iodine-containing   
  Radiographic contrast agents)
  Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma).  Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
  Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
  Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism.  Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents.  Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport  - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
  Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
  Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
  Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
  Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4, and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result  in hypothyroidism
  Carbamazepine
Hydantoins
Phenobarbital
Rifampin
  Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5’-deiodinase activity
  Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
  Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4  levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
  Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
  Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
  Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors
  (SSRIs; e.g., Sertraline)
  Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of  tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
  Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
  Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
  Cardiac Glycosides   Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
  Cytokines
- Interferon-α
- Interleukin-2
  Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
  Growth Hormones
- Somatrem
- Somatropin
  Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
  Ketamine   Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
  Methylxanthine Bronchodilators
- (e.g., Theophylline)
  Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
  Radiographic Agents   Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
  Sympathomimetics   Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
  Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
  These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.


Table name:
Table 18. Summary of Effect of Co-administered Drugs on Exposure to Active Moiety (Risperidone + 9- Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Co-administered Drug  Dosing Schedule  Effect on Active Moeity (Risperidone + 9-Hydroxy-Risperidone (RatioChange relative to reference Risperidone Dose Recommendation 
  Co-administered Drug  Risperidone  AUC  Cmax   
Enzyme (CYP2D6) Inhibitors           
Fluoxetine  20 mg/day  2 or 3 twice daily  1.4  1.5  Re-evaluate dosing. Do not exceed 8 mg/day 
Paroxetine  10 mg/day  4 mg/day  1.3   - Re-evaluate dosing. Do not exceed 8 mg/day
  20 mg/day  4 mg/day  1.6   -   
  40 mg/day  4 mg/day  1.8   -  
Enzyme (CYP3A/PgP inducers) Inducers          
Carbamazepine 573 ± 168 mg/day  3 mg twice daily  0.51 0.55  Titrate dose upwards. Do not exceed twice the patient’s usual dose 
Enzyme (CYP3A) Inhibitors          
Ranitidine  150 mg twice daily  1 mg single dose  1.2  1.4  Dose adjustment not needed 
Cimetidine  400 mg twice daily  1 mg single dose  1.1  1.3  Dose adjustment not needed 
Erythromycin  500 mg four times daily  1 mg single dose  1.1  0.94  Dose adjustment not needed 
Other Drugs           
Amitriptyline  50 mg twice daily  3 mg twice daily  1.2  1.1  Dose adjustment not needed 


Table name:
 a = Plasma concenrtration increased 25% in some patients, generally those on a twice a day dosing regimen
 of phenytoin.
 b = Is not administered but is an active metabolite of carbamazepine.
 NC = Less than 10% change in plasma concentration.
 NE = Not Evaluated
 AED Co-administered
 AED Concentration
 Topiramate Concentration
 Phenytoin
 NC or 25% increasea
 48% decrease
 Carbamazepine (CBZ)
 NC
 40% decrease
 CBZ epoxideb
 NC
 NE
 Valproic acid
 11% decrease
 14% decrease
 Phenobarbital
 NC
 NE
 Primidone
 NC
 NE
 Lamotrigine
 NC at TPM doses up to 400 mg/day
 13% decrease


Table name:
Table 3Drugs that Can Increase the Risk of Bleeding
Drug  Class
Specific  Drugs
Anticoagulants 
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin 
Antiplatelet Agents 
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine 
Nonsteroidal Anti-Inflammatory Agents 
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac 
Serotonin Reuptake Inhibitors 
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone 


Table name:
Interacting Drug Interaction
Theophylline Serious and fatal reactions. Avoid concomitant use. Monitor serum level ( 7)
Warfarin Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding ( 7)
Antidiabetic agents Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose ( 7)
Phenytoin Monitor phenytoin level ( 7)
Methotrexate Monitor for methotrexate toxicity ( 7)
Cyclosporine May increase serum creatinine. Monitor serum creatinine ( 7)
Multivalent cation-containing products including antacids, metal cations or didanosine Decreased ciprofloxacin tablets absorption. Take 2 hours before or 6 hours after ciprofloxacin tablets ( 7)


Table name:
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
AED Coadministered AED Concentration Topiramate Concentration
Phenytoin NC or 25% increasea 48% decrease
Carbamazepine (CBZ) NC 40% decrease
CBZ epoxideb NC NE
Valproic acid 11% decrease 14% decrease
Phenobarbital NC NE
Primidone NC NE
Lamotrigine NC at TPM doses up to 400 mg/day 13% decrease


Table name:
AED  Co - administered
AED  Concentration
Topiramate  Concentration
Phenytoin
NCor25%increase a
48%decrease
Carbamazepine(CBZ)
NC
40%decrease
CBZepoxide b
NC 
            NE
Valproic acid
11%decrease
14%decrease
Phenobarbital
NC
            NE
Primidone
NC
           NE
Lamotrigine
NCatTPM dosesupto400  mg/day 
         13%decrease


Table name:
Table 18. Summary of Effect of Co-administered Drugs on Exposure to Active Moiety (Risperidone + 9- Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Co-administered Drug  Dosing Schedule  Effect on Active Moeity (Risperidone + 9-Hydroxy-Risperidone (RatioChange relative to reference Risperidone Dose Recommendation 
  Co-administered Drug  Risperidone  AUC  Cmax   
Enzyme (CYP2D6) Inhibitors           
Fluoxetine  20 mg/day  2 or 3 twice daily  1.4  1.5  Re-evaluate dosing. Do not exceed 8 mg/day 
Paroxetine  10 mg/day  4 mg/day  1.3   - Re-evaluate dosing. Do not exceed 8 mg/day
  20 mg/day  4 mg/day  1.6   -   
  40 mg/day  4 mg/day  1.8   -  
Enzyme (CYP3A/PgP inducers) Inducers          
Carbamazepine 573 ± 168 mg/day  3 mg twice daily  0.51 0.55  Titrate dose upwards. Do not exceed twice the patient’s usual dose 
Enzyme (CYP3A) Inhibitors          
Ranitidine  150 mg twice daily  1 mg single dose  1.2  1.4  Dose adjustment not needed 
Cimetidine  400 mg twice daily  1 mg single dose  1.1  1.3  Dose adjustment not needed 
Erythromycin  500 mg four times daily  1 mg single dose  1.1  0.94  Dose adjustment not needed 
Other Drugs           
Amitriptyline  50 mg twice daily  3 mg twice daily  1.2  1.1  Dose adjustment not needed 


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
↓= Decreased (induces lamotrigine glucuronidation).
↑= Increased (inhibits lamotrigine glucuronidation).
?= Conflicting data.
Concomitant  Drug
Effect  on  Concentration  of  Lamotrigine  or  Concomitant  Drug
Clinical  Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 
150 mcg levonorgestrel 
↓ lamotrigine 
↓ levonorgestrel 
Decreased lamotrigine concentrations approximately 50%. 
Decrease in levonorgestrel component by 19%. 
Carbamazepine and carbamazepine epoxide 
↓ lamotrigine 
? carbamazepine epoxide 
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. 
May increase carbamazepine epoxide levels. 
Lopinavir/ritonavir
↓ lamotrigine 

Decreased lamotrigine concentration approximately 50%. 

Atazanavir/ritonavir
↓ lamotrigine 

Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone
↓ lamotrigine
Decreased lamotrigine concentration approximately 40%.
Phenytoin
↓ lamotrigine
Decreased lamotrigine concentration approximately 40%.
Rifampin
↓ lamotrigine
Decreased lamotrigine AUC approximately 40%.
Valproate
↑ lamotrigine  
? valproate




Increased lamotrigine concentrations slightly more than 2-fold. 
There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.


Table name:
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors          (e.g., itraconazole,    ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin,    HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Grapefruit juice Avoid grapefruit juice


Table name:
AED Coadministered AED Concentration Topiramate Concentration
Phenytoin
NC or 25% increase Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
48% decrease


Carbamazepine (CBZ)
NC
40% decrease
CBZ epoxide Is not administered but is an active metabolite of carbamazepine.
NC
NE
Valproic acid
11% decrease
14% decrease
Phenobarbital
NC
NE
Primidone
NC
NE
Lamotrigine
NC at TPM doses up to 400 mg/day
13% decrease


Table name:
Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) VIAGRA 100 mg
Supine 7.9 (4.6, 11.1)
Standing

4.3 (-1.8,10.3)



Table name:
Interacting Drug Interaction
Theophylline Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin Monitor phenytoin level (7)
Methotrexate Monitor for methotrexate toxicity (7)
Cyclosporine May increase serum creatinine. Monitor serum creatinine (7)
Multivalent cation-containing products including antacids, metal cations or didanosine Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin (7)


Table name:
Table 3 Clinically Significant Drug Interactions with Meloxicam
Drugs that Interfere with Hemostasis
Clinical Impact:
Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.
Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. 
Intervention: 
Monitor patients with concomitant use of meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)]. 
Aspirin 
Clinical Impact: 
Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)]. 
Intervention: 
Concomitant use of meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. 

Meloxicam is not a substitute for low dose aspirin for cardiovascular protection. 
ACE Inhibitors, Angiotensin Receptor Blockers, or Beta-Blockers 
Clinical Impact: 

NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). 
In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. 
Intervention: 

During concomitant use of meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. 
During concomitant use of meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. 
When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. 
Diuretics 

Clinical Impact: 

Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. 
Intervention: 

During concomitant use of meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)]. 
Lithium 
Clinical Impact: 

NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [see Clinical Pharmacology (12.3)]. 
Intervention: 

During concomitant use of meloxicam and lithium, monitor patients for signs of lithium toxicity. 
Methotrexate 
Clinical Impact: 

Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: 

During concomitant use of meloxicam and methotrexate, monitor patients for methotrexate toxicity. 
Cyclosporine 

Clinical Impact: 

Concomitant use of meloxicam and cyclosporine may increase cyclosporine’s nephrotoxicity. 
Intervention: 

During concomitant use of meloxicam and cyclosporine, monitor patients for signs of worsening renal function. 
NSAIDs and Salicylates 

Clinical Impact: 

Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)]. 
Intervention: 

The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended. 
Pemetrexed 

Clinical Impact: 

Concomitant use of meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). 
Intervention: 

During concomitant use of meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended. 


Table name:
Drug Interactions Associated with Increased Risk of  Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice Avoid grapefruit juice


Table name:
Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.*
albuterol, systemic and inhaled felodipinefinasteride nizatidinenorfloxacin
amoxicillin hydrocortisone ofloxacin
ampicillin, with or without sulbactam isoflurane isoniazid omeprazole prednisone, prednisolone
atenolol isradipine ranitidine
azithromycin influenze vaccine rifabutin
caffeine, dietary ingestion ketoconazo lelomefloxacin Roxithromycin sorbitol (purgative doses do onot inhibit theophylline absorption)
cefaclor mebendazole
co-trimoxazole (trimethoprim and sulfamethoxazole) medroxyprogesteronemethylprednisolone sucralfate
diltiazem metronidazole terbutaline, systemic
dirithromycin metoprolol terfenadine
enflurane nadolol tetracycline
famotidine nifedipine tocainide


Table name:
Table 5: Summary of Effect of Coadministered Drugs on Exposure to Asenapine in Healthy Volunteers
Coadministered drug
(Postulated effect on CYP450/UGT)
Dose schedules Effect on asenapine pharmacokinetics Recommendation
Coadministered drug Asenapine Cmax AUC0-∞
Fluvoxamine
(CYP1A2 inhibitor)
25 mg twice daily for 8 days 5-mg Single Dose +13% +29% Coadminister with cautionThe full therapeutic dose of fluvoxamine would be expected to cause a greater increase in asenapine plasma concentrations. AUC: Area under the curve.
Paroxetine
(CYP2D6 inhibitor)
20 mg once daily for 9 days 5-mg Single Dose –13% –9% No SAPHRIS dose adjustment required [see Drug Interactions (7.2)]
Imipramine
(CYP1A2/2C19/3A4 inhibitor)
75-mg Single Dose 5-mg Single Dose +17% +10% No SAPHRIS dose adjustment required
Cimetidine
(CYP3A4/2D6/1A2 inhibitor)
800 mg twice daily for 8 days 5-mg Single Dose –13% +1% No SAPHRIS dose adjustment required
Carbamazepine
(CYP3A4 inducer)
400 mg twice daily for 15 days
5-mg Single Dose –16% –16% No SAPHRIS dose adjustment required
Valproate
(UGT1A4 inhibitor)
500 mg twice daily for 9 days 5-mg Single Dose 2% –1% No SAPHRIS dose adjustment required


Table name:
CYP2C19 or CYP3A4 Inducers
Clinical Impact:   Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology (12.3)].
Intervention:   St. John’s Wort, rifampin: Avoid concomitant use with omeprazole [see Warnings and Precautions (5.9)]. Ritonavir-containing products: see prescribing information for specific drugs.
 CYP2C19 or CYP3A4 Inhibitors
Clinical Impact: Increased exposure of omeprazole [see Clinical Pharmacology (12.3)].
Intervention:   Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered. See prescribing information for voriconazole.


Table name:
Table II Clinically significant drug interactions with theophylline*.
  * Refer to PRECAUTIONS, Drug Interactions for further information regarding table.
  ** Average effect on steady state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.
 Drug  Type of Interaction  Effect**
 Adenosine  Theophylline blocks adenosine receptors.  Higher doses of adenosine may be required to achieve desired effect.
 Alcohol  A single large dose of alcohol (3 ml/kg of whiskey) decreases theophylline clearance for up to 24 hours.  30% increase
 Allopurinol  Decreases theophylline clearance at allopurinol doses ≥600 mg/day.  25% increase
 Aminoglutethimide  Increase theophylline clearance by induction of microsomal enzyme activity.  25% decrease
 Carbamazepine  Similar to aminoglutethimide.  30% decrease
 Cimetidine  Decreases theophylline clearance by inhibiting cytochrome P450 1A2.  70% increase
 Ciprofloxacin  Similar to cimetidine.  40% increase
 Clarithromycin  Similar to erythromycin.  25% increase
 Diazepam  Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant while, theophylline blocks adenosine receptors  Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
 Disulfiram  Decreases theophylline clearance by inhibiting hydroxylation and demethylation  50% increase
 Enoxacin  Similar to cimetidine.  300% increase
 Ephedrine  Synergistic CNS effects of nausea, nervousness, and insomnia.  Increased frequency of nausea, nervousness, and insomnia
 Erythromycin  Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3.  35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
 Estrogen  Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown.  30% increase
 Flurazepam  Similar to diazepam.  Similar to diazepam.
 Fluvoxamine  Similar to cimetidine  Similar to cimetidine
 Halothane  Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines.  Increased risk of ventricular arrhythmias.
 Interferon, human recombinant alpha-A  Decreases theophylline clearance.  100% increase
 Isoproterenol (IV)  Increases theophylline clearance.  20% decrease
 Ketamine  Pharmacologic  May lower theophylline seizure threshold.
 Lithium  Theophylline increases renal lithium clearance.  Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
 Lorazepam  Similar to diazepam.  Similar to diazepam.
 Methotrexate (MTX)  Decreases theophylline clearance.  20% increase after low dose MTX, higher dose MTX may have a greater effect.
 Mexiletine.  Similar to disulfiram.  80% increase
 Midazolam  Similar to diazepam.  Similar to diazepam.
 Moricizine  Increases theophylline clearance.  25% decrease
 Pancuronium  Theophylline may antagonize nondepolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition.  Larger dose of pancuronium may be required to achieve neuromuscular blockade.
 Pentoxifylline  Decreases theophylline clearance.  30% increase
 Phenobarbital (PB)  Similar to aminoglutethimide.  25% decrease after two weeks of concurrent PB.
 Phenytoin  Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption.  Serum theophylline and
phenytoin concentrations decrease about 40%.
 Propafenone  Decreases theophylline clearance and pharmacologic interaction.  40% increase. Beta-2
blocking effect may decrease efficacy of theophylline.
 Propranolol  Similar to cimetidine and pharmacologic interaction  100% increase Beta-2 blocking effect may decrease efficacy of theophylline.
 Rifampin  Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity.  20-40% decrease
 Sulfinpyrazone  Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline.  20% decrease
 Tacrine  Similar to cimetidine, also increase renal clearance of theophylline.  90% increase
 Thiabendazole  Decreases theophylline clearance.  190% increase
 Ticlopidine  Decreases theophylline clearance.  60% increase
 Troleandomycin  Similar to erythromycin.  33-100% increase depending on
troleandomycin dose.
 Verapamil  Similar to disulfiram.  20% increase


Table name:
Drugs that Affect Renal          
Function
A decline in GFR or tubular secretion, as from ACE inhibitors,          
angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs
[NSAIDs], COX-2 inhibitors may impair the excretion of digoxin.
Antiarrthymics Dofetilide Concomitant administration with digoxin was associated with a higher rate of torsades de pointes.
  Sotalol  Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
  Dronedarone Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone
Analog
Teriparatide Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement Thyroid Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics Epinephrine Norepinephrine Dopamine Can increase the risk of cardiac arrhythmias.
Neuromuscular Blocking
Agents
Succinylcholine May cause sudden extrusion of potassium from muscle cells, causing arrhythmias in patients taking digoxin.
Supplements Calcium If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers
and calcium channel
blockers
  Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.


Table name:
DRUG DESCRIPTION OF INTERACTION
Heparin Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparintreated patients.
Pyrazinamide Inhibits pyrazinamide induced hyperuricemia.
Uricosuric Agents Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited.


Table name:
Summary of AED interactions with topiramate ( 7.1).
AED Co-administered AED Concentration Topiramate Concentration
Phenytoin NC or 25% increase a 48% decrease
Carbamazepine (CBZ) NC 40% decrease
CBZ epoxide b NC NE
Valproic acid 11% decrease 14% decrease
Phenobarbital NC NE
Primidone NC NE
Lamotrigine NC at TPM doses up to 400mg/day 13% decrease


Table name:
Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s) Recommendation Comments
Tizanidine Contraindicated Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)].
Theophylline Avoid Use (Plasma Exposure Likely to be Increased and Prolonged) Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions (5.6).]
Drugs Known to Prolong QT Interval Avoid Use Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.10) and Use in Specific Populations (8.5)].
Oral antidiabetic drugs Use with caution Glucose-lowering effect potentiated Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported . Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs. [see Adverse Reactions (6.1).]
Phenytoin Use with caution Altered serum levels of phenytoin (increased and decreased) To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after coadministration of ciprofloxacin with phenytoin.
Cyclosporine Use with caution (transient elevations in serum creatinine) Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs Use with caution (Increase in anticoagulant effect) The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole Use with caution Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after coadministration with ciprofloxacin [see Warnings and Precautions (5.15)].
Clozapine Use with caution Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs Use with caution Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil Use with caution 2-fold increase in exposure Monitor for sildenafil toxicity (see Pharmacokinetics -(12.3)-] .
Duloxetine Avoid Use 5-fold increase in duloxetine exposure If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx ® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products) Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2)]. Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels) Potentiation of ciprofloxacin toxicity may occur.


Table name:
Table 9. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class:
Drug Name
Effect on Concentration of Lopinavir or Concomitant Drug Clinical Comments
HIV-1 Antiviral Agents
HIV-1 Protease Inhibitor:
fosamprenavir/ritonavir
↓ amprenavir
↓ lopinavir
An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor:
indinavir*
↑ indinavir Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily [see Clinical Pharmacology (12.3)]. KALETRA once daily has not been studied in combination with indinavir.
HIV-1 Protease Inhibitor:
nelfinavir*
↑ nelfinavir
↑ M8 metabolite of nelfinavir
↓ lopinavir
KALETRA should not be administered once daily in combination with nelfinavir
[see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].

HIV-1 Protease Inhibitor:
ritonavir*
↑ lopinavir Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor:
saquinavir*
↑ saquinavir The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily.
KALETRA once daily has not been studied in combination with saquinavir.
HIV-1 Protease Inhibitor:
tipranavir
↓ lopinavir AUC and Cmin KALETRA should not be administered with tipranavir (500 mg twice daily) co-administered with ritonavir (200 mg twice daily).
HIV CCR5 – Antagonist:
maraviroc
↑ maraviroc Concurrent administration of maraviroc with KALETRA will increase plasma levels of maraviroc. When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for Selzentry® (maraviroc).
Non-nucleoside Reverse Transcriptase Inhibitors:
efavirenz*,
nevirapine*
↓ lopinavir KALETRA dose increase is recommended in all patients [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
Increasing the dose of KALETRA tablets to 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) twice daily co-administered with efavirenz resulted in similar lopinavir concentrations compared to KALETRA tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz.
Increasing the dose of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice daily co-administered with efavirenz resulted in significantly higher lopinavir plasma concentrations compared to KALETRA tablets 400/100 mg twice daily without efavirenz.
KALETRA should not be administered once daily in combination with efavirenz or nevirapine
[see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
Non-nucleoside Reverse Transcriptase Inhibitor:
delavirdine
↑ lopinavir Appropriate doses of the combination with respect to safety and efficacy have not been established.
Nucleoside Reverse Transcriptase Inhibitor:
didanosine
  KALETRA tablets can be administered simultaneously with didanosine without food.
For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food).
Nucleoside Reverse Transcriptase Inhibitor:
tenofovir
↑ tenofovir KALETRA increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir.
Nucleoside Reverse Transcriptase Inhibitors:
abacavir
zidovudine
↓ abacavir
↓ zidovudine
KALETRA induces glucuronidation; therefore, KALETRA has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown.
Other Agents
Antiarrhythmics e.g.:
amiodarone,
bepridil,
lidocaine (systemic),
quinidine
↑ antiarrhythmics Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA.
Anticancer Agents:
vincristine,
vinblastine,
dasatinib,
nilotinib
↑ anticancer agents Concentrations of these drugs may be increased when co-administered with KALETRA resulting in the potential for increased adverse events usually associated with these anticancer agents.
For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when KALETRA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor.
A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as KALETRA. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions.
Anticoagulants:
warfarin,
rivaroxaban
  ↑ rivaroxaban Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.

Avoid concomitant use of rivaroxaban and KALETRA. Co-administration of KALETRA and rivaroxaban is expected to result in increased exposure of rivaroxaban which may lead to risk of increased bleeding.
Anticonvulsants:
carbamazepine,
phenobarbital,
phenytoin
↓ lopinavir
↓ phenytoin
KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution.
KALETRA should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin.

In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA.
Anticonvulsants:
lamotrigine,
valproate
↓ lamotrigine
↓ or ↔ valproate
Co-administration of KALETRA and lamotrigine or valproate may decrease the exposure of lamotrigine or valproate. A dose increase of lamotrigine or valproate may be needed when co-administered with KALETRA and therapeutic concentration monitoring for lamotrigine may be indicated; particularly during dosage adjustments [see Clinical Pharmacology (12.3)].
Antidepressant:
bupropion
↓ bupropion
↓ active metabolite,
hydroxybupropion
Concurrent administration of bupropion with KALETRA may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion.
Antidepressant:
trazodone
↑ trazodone Concomitant use of trazodone and KALETRA may increase concentrations of trazodone. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered.
Anti-infective:
clarithromycin
↑ clarithromycin For patients with renal impairment, the following dosage adjustments should be considered:
  • For patients with CLCR 30 to 60 mL/min the dose
    of clarithromycin should be reduced by 50%.
  • For patients with CLCR < 30 mL/min the dose
    of clarithromycin should be decreased by 75%.

No dose adjustment for patients with normal renal function is necessary.
Antifungals:
ketoconazole*,
itraconazole,
voriconazole
↑ ketoconazole
↑ itraconazole
↓ voriconazole
High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended.
Co-administration of voriconazole with KALETRA has not been studied. However, a study has been shown that administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%; therefore, co-administration of KALETRA and voriconazole may result in decreased voriconazole concentrations and the potential for decreased voriconazole effectiveness and should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Otherwise, alternative antifungal therapies should be considered in these patients.
Anti-gout:
colchicine
↑ colchicine Patients with renal or hepatic impairment should not be given colchicine with KALETRA.

Treatment of gout flares-co-administration of colchicine in patients on KALETRA:

0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days.

Prophylaxis of gout flares-co-administration of colchicine in patients on KALETRA:

If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.

If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.

Treatment of familial Mediterranean fever (FMF)-co-administration of colchicine in patients on KALETRA:

Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Antimycobacterial:
rifabutin*
↑ rifabutin and rifabutin metabolite Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary.
Antimycobacterial:
rifampin
↓ lopinavir May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents. A study evaluated combination of rifampin 600 mg once daily, with KALETRA 800/200 mg twice daily or KALETRA 400/100 mg + ritonavir 300 mg twice daily. Pharmacokinetic and safety results from this study do not allow for a dose recommendation. Nine subjects (28%) experienced a ≥ grade 2 increase in ALT/AST, of which seven (21%) prematurely discontinued study per protocol. Based on the study design, it is not possible to determine whether the frequency or magnitude of the ALT/AST elevations observed is higher than what would be seen with rifampin alone [see Clinical Pharmacology (12.3) for magnitude of interaction].
Antiparasitic:
atovaquone
↓ atovaquone Clinical significance is unknown; however, increase in atovaquone doses may be needed.
Benzodiazepines: parenterally administered midazolam ↑ midazolam Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, KALETRA should not be given with orally administered midazolam [see Contraindications (4)]. If KALETRA is co-administered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.
Contraceptive:
ethinyl estradiol*
↓ ethinyl estradiol Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended.
Corticosteroids (systemic): e.g.
budesonide,
dexamethasone,
prednisone
↓ lopinavir
↑ glucocorticoids
Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly.
Concomitant use may result in increased steroid concentrations and reduced serum cortisol concentrations. Concomitant use of glucocorticoids that are metabolized by CYP3A, particularly for long-term use, should consider the potential benefit of treatment versus the risk of systemic corticosteroid effects. Concomitant use may increase the risk for development of systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression.
Dihydropyridine Calcium Channel Blockers: e.g.
felodipine,
nifedipine,
nicardipine
↑ dihydropyridine calcium channel blockers Caution is warranted and clinical monitoring of patients is recommended.
Disulfiram/metronidazole   KALETRA oral solution contains alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).
Endothelin Receptor Antagonists:
bosentan
↑ bosentan Co-administration of bosentan in patients on KALETRA:

In patients who have been receiving KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

Co-administration of KALETRA in patients on bosentan:

Discontinue use of bosentan at least 36 hours prior to initiation of KALETRA.

After at least 10 days following the initiation of KALETRA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
HCV-Protease Inhibitor:
boceprevir
↓ lopinavir
↓ boceprevir
↓ ritonavir
It is not recommended to co-administer KALETRA and boceprevir. Concomitant administration of KALETRA and boceprevir reduced boceprevir, lopinavir and ritonavir steady-state exposures [see Clinical Pharmacology (12.3)].
HCV-Protease Inhibitor:
telaprevir
↓ telaprevir
↔ lopinavir
It is not recommended to co-administer KALETRA and telaprevir. Concomitant administration of KALETRA and telaprevir reduced steady-state telaprevir exposure, while the steady-state lopinavir exposure was not affected [see Clinical Pharmacology (12.3)].
HMG-CoA Reductase Inhibitors:
atorvastatin
rosuvastatin
↑ atorvastatin
↑ rosuvastatin
Use atorvastatin with caution and at the lowest necessary dose. Titrate rosuvastatin dose carefully and use the lowest necessary dose; do not exceed rosuvastatin 10 mg/day. See Drugs with No Observed or Predicted Interactions with KALETRA (7.4) and Clinical Pharmacology (12.3) for drug interaction data with other HMG-CoA reductase inhibitors.
Immunosuppressants: e.g.
cyclosporine,
tacrolimus,
sirolimus
↑ immunosuppressants Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA.
Inhaled or Intranasal Steroids e.g.:
fluticasone,
budesonide
↑ glucocorticoids Concomitant use of KALETRA and fluticasone or other glucocorticoids that are metabolized by CYP3A is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects. Concomitant use may result in increased steroid concentrations and reduce serum cortisol concentrations.
Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during postmarketing use in patients when certain ritonavir-containing products have been co-administered with fluticasone propionate or budesonide.
Long-acting beta-adrenoceptor Agonist:
salmeterol
↑ salmeterol Concurrent administration of salmeterol and KALETRA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Narcotic Analgesics:
methadone,*
fentanyl
↓ methadone
↑ fentanyl
Dosage of methadone may need to be increased when co-administered with KALETRA.
Concentrations of fentanyl are expected to increase. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with KALETRA.
PDE5 inhibitors:
avanafil,
sildenafil,
tadalafil,
vardenafil
↑ avanafil
↑ sildenafil
↑ tadalafil
↑ vardenafil
Do not use KALETRA with avanafil because a safe and effective avanafil dosage regimen has not been established.
Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs is expected to substantially increase their concentrations and may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection.

Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH):

Sildenafil (Revatio®) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with KALETRA [see Contraindications (4)].

The following dose adjustments are recommended for use of tadalafil (Adcirca®) with KALETRA:

Co-administration of ADCIRCA in patients on KALETRA:

In patients receiving KALETRA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Co-administration of KALETRA in patients on ADCIRCA:

Avoid use of ADCIRCA during the initiation of KALETRA. Stop ADCIRCA at least 24 hours prior to starting KALETRA. After at least one week following the initiation of KALETRA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Use of PDE5 inhibitors for erectile dysfunction:

It is recommended not to exceed the following doses:
  • Sildenafil: 25 mg every 48 hours
  • Tadalafil: 10 mg every 72 hours
  • Vardenafil: 2.5 mg every 72 hours

Use with increased monitoring for adverse events.
*   see Clinical Pharmacology (12.3) for magnitude of interaction.


Table name:
Interacting Drug
Interaction
Theophylline
Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin
Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents
Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin
Monitor phenytoin level (7)
Methotrexate
Monitor for methotrexate toxicity (7)
Cyclosporine
May increase serum creatinine. Monitor serum creatinine (7)
Multivalent cation-containing products including antacids, metal cations or didanosine
Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin (7)


Table name:
Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme
Inhibitors
Inducers
CYP2C9 
amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast
aprepitant, bosentan, carbamazepine, phenobarbital, rifampin 
CYP1A2 
acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton
montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking 
CYP3A4 
alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton
armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide 


Table name:
Table 6. Drugs That Should Not Be Coadministered With RESCRIPTOR
Drug Class: Drug Name Clinical Comment
Anticonvulsant agents: Phenytoin, phenobarbital, carbamazepine May lead to loss of virologic response and possible resistance to RESCRIPTOR or to the class of NNRTIs.
Antihistamines: Astemizole, terfenadine CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Antimycobacterials: Rifabutin,a rifampin a May lead to loss of virologic response and possible resistance to RESCRIPTOR or to the class of NNRTIs or other coadministered antiviral agents.
Ergot Derivatives: Dihydroergotamine, ergonovine, ergotamine, methylergonovine CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
GI motility agent: Cisapride CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Herbal Products: St. John’s wort
(Hypericum perforatum)
May lead to loss of virologic response and possible resistance to RESCRIPTOR or to the class of NNRTIs.
HMG-CoA reductase inhibitors: Lovastatin, simvastatin Potential for serious reactions such as risk of myopathy including rhabdomyolysis.
Neuroleptic: Pimozide CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Sedative/hypnotics: Alprazolam, midazolam, triazolam CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression.


Table name:
Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine Do not exceed 10 mg atorvastatin daily
Clarithromycin, itraconazole, HIV protease inhibitors (ritonavir plus saquinavir or lopinavir plus ritonavir) Caution when exceeding doses > 20 mg atorvastatin daily. The lowest dose necessary should be used.


Table name:
Drug/Drug Class (Mechanism of Interaction by the Drug) Voriconazole Plasma Exposure
(Cmax and AUC
τ after 200 mg q12h)
Recommendations for Voriconazole Dosage Adjustment/Comments
Rifampin* and Rifabutin* (CYP450 Induction) Significantly Reduced Contraindicated
Efavirenz (400 mg q24h)** (CYP450 Induction)

Efavirenz (300 mg q24h)** (CYP450 Induction)
Significantly Reduced



Slight Decrease in AUCτ
Contraindicated



When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)** (CYP450 Induction)
Low-dose Ritonavir (100 mg q12h)** (CYP450 Induction)
Significantly Reduced


Reduced
Contraindicated


Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Carbamazepine (CYP450 Induction) Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction Contraindicated
Long Acting Barbiturates (CYP450 Induction) Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction Contraindicated
Phenytoin* (CYP450 Induction) Significantly Reduced Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg)
St. John’s Wort (CYP450 inducer; P-gp inducer) Significantly Reduced Contraindicated
Oral Contraceptives** containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition) Increased Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole** (CYP2C9, CYP2C19 and CYP3A4 Inhibition) Significantly Increased Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole
Other HIV Protease Inhibitors (CYP3A4 Inhibition) In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure
In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)
No dosage adjustment in the voriconazole dosage needed when coadministered with
indinavir

Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIs*** (CYP3A4 Inhibition or CYP450 Induction) In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure)
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure)
Frequent monitoring for adverse events and toxicity related to voriconazole Careful assessment of voriconazole effectiveness


Table name:
Concomitant Drug Name or Drug Class
Clinical Rationale
Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) 
The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].
With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)
The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].
With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Antihypertensive Drugs
Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.
Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.8)]. 


Table name:
Table 18Summary of Effect of Coadministered Drugs on Exposure to Active Moiety(Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients withSchizophrenia
*Change relative to reference
Coadministered Drug
Dosing Schedule

Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*)





Risperidone Dose Recommendation


Coadministered Drug
Risperidone
AUC
C m a x

Enzyme (CYP2D6)  Inhibitors 






Fluoxetine 
20 mg/day
2 or 3 mg twice daily

1.4
1.5
Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine 
10 mg/day
4 mg/day
1.3
-
Re-evaluate dosing. 

20 mg/day
4 mg/day
1.6
-
Do not exceed 8 mg/day

40 mg/day
4 mg/day
1.8
-

Enzyme (CYP3A/  PgP inducers) 






Carbamazepine 
573 ± 168 mg/day
3 mg twice daily
0.51
0.55
Titrate dose upwards. Do not exceed twice the patient’s usual dose

Enzyme (CYP3A)  Inhibitors 






Ranitidine 
150 mg twice daily
1 mg single dose
1.2
1.4
Dose adjustment not needed

Cimetidine 
400 mg twice daily
1 mg single dose
1.1
1.3
Dose adjustment not needed

Erythromycin 
500 mg four times daily

1 mg single dose
1.1
0.94
Dose adjustment not needed

Other Drugs 





Amitriptyline 
50 mg twice daily
3 mg twice daily
1.2
1.1
Dose adjustment not needed



Table name:
Interacting Drug Interaction
Theophylline Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin Monitor phenytoin level (7)
Methotrexate Monitor for methotrexate toxicity (7)
Cyclosporine May increase serum creatinine. Monitor serum creatinine (7)
Multivalent cation-containing products including antacids, metal cations or didanosine Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin (7)


Table name:
Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline. Refer to PRECAUTIONS , Drug Interactions for information regarding table.
albuterol, lomefloxacin
   systemic and inhaled mebendazole
amoxicillin medroxyprogesterone
ampicillin, methylprednisolone
   with or without sulbactam metronidazole
atenolol metoprolol
azithromycin nadolol
caffeine, nifedipine
   dietary ingestion nizatidine
cefaclor norfloxacin
co-trimoxazole ofloxacin
   (trimethoprim and omeprazole
   sulfamethoxazole) prednisone, prednisolone
diltiazem ranitidine
dirithromycin rifabutin
enflurane roxithromycin
famotidine sorbitol
felodipine    (purgative doses do not
finasteride    inhibit theophylline
hydrocortisone    absorption)
isoflurane sucralfate
isoniazid terbutaline, systemic
isradipine terfenadine
influenza vaccine tetracycline
ketoconazole tocainide


Table name:
Digoxin
Clinical Impact:
The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:
During concomitant use of naproxen and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:
NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:
During concomitant use of naproxen and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:
Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:
During concomitant use of naproxen and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:
Concomitant use of naproxen and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:
During concomitant use of naproxen and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:
Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:
The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:
Concomitant use of naproxen and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:
During concomitant use of naproxen and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
* For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Interacting Agents
Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol
Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone
Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine
Do not exceed 20 mg simvastatin daily
Lomitapide
For patients with HoFH, do not exceed 20 mg simvastatin daily*
Grapefruit juice
Avoid grapefruit juice


Table name:
Interacting  Agents 
Prescribing  Recommendations 
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, 
posaconazole, voriconazole, erythromycin, clarithromycin, 
telithromycin, HIV protease inhibitors, boceprevir, telaprevir, 
nefazodone, cobicistatcontaining products), gemfibrozil, 
cyclosporine, danazol 
 Contraindicated with simvastatin 
Verapamil, diltiazem, dronedarone
Do not exceed 10 mg simvastatin daily 
Amiodarone, amlodipine, ranolazine
Do not exceed 20 mg simvastatin daily 
Lomitapide
For patients with HoFH, do not exceed 
20 mg simvastatin dailyFor patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice 
Avoid grapefruit juice  


Table name:
Table 18Summary of Effect of Coadministered Drugs on Exposure to Active Moiety(Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients withSchizophrenia
*Change relative to reference
Coadministered Drug
Dosing Schedule

Effect on Active
Moiety
(Risperidone + 9-
Hydroxy-
Risperidone (Ratio*)

Risperidone Dose
Recommendation

Coadministered Drug
Risperidone
AUC
C m a x

Enzyme (CYP2D6) 
Inhibitors 





Fluoxetine 
20 mg/day
2 or 3 mg twice
daily
1.4
1.5
Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine 
10 mg/day
4 mg/day
1.3
-
Re-evaluate dosing. 

20 mg/day
4 mg/day
1.6
-
Do not exceed 8 mg/day

40 mg/day
4 mg/day
1.8
-

Enzyme (CYP3A/ 
PgP inducers) 





Carbamazepine 
573 ± 168 mg/day
3 mg twice daily
0.51
0.55
Titrate dose upwards.
Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) 
Inhibitors 





Ranitidine 
150 mg twice daily
1 mg single dose
1.2
1.4
Dose adjustment not
needed
Cimetidine 
400 mg twice daily
1 mg single dose
1.1
1.3
Dose adjustment not
needed
Erythromycin 
500 mg four times
daily
1 mg single dose
1.1
0.94
Dose adjustment not
needed
Other Drugs 





Amitriptyline 
50 mg twice daily
3 mg twice daily
1.2
1.1
Dose adjustment not
needed


Table name:
NA – Not available/reported
Digoxin concentrations increased greater than 50%
   Digoxin Serum   
Concentration Increase
   Digoxin AUC   
Increase
Recommendations
Amiodarone 70% NA Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring.
Captopril 58% 39%
Clarithromycin NA 70%
Dronedarone NA 150%
Gentamicin 129-212% NA
Erythromycin 100% NA
Itraconazole 80% NA
Nitrendipine 57% 15%
Propafenone NA 60-270%
Quinidine 100% NA
Ranolazine 50% NA
Ritonavir NA 86%
Tetracycline 100% NA
Verapamil 50-75% NA
Digoxin concentrations increased less than 50%
Atorvastatin 22% 15% Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring.
Carvedilol 16% 14%
Diltiazem 20% NA
Indomethacin 40% NA
Nefazodone 27% 15%
Nifedipine 45% NA
Propantheline 24% 24%
Quinine NA 33%
Saquinavir 27% 49%
Spironolactone      25% NA
Telmisartan 20-49% NA
Tolvaptan 30% NA
Trimethoprim 22-28% NA
Digoxin concentrations increased, but magnitude is unclear
Alprazolam, azithromycin, cyclosporine, diclofenac,
diphenoxylate, epoprostenol, esomeprazole, ibuprofen,
ketoconazole, lansoprazole, metformin, omeprazole,
rabeprazole,
Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin concentrations decreased
Acarbose, activated charcoal, albuterol, antacids, certain
cancer chemotherapy or radiation therapy, cholestyramine,
colestipol, extenatide, kaolin-pectin, meals high in bran,
metoclopramide, miglitol, neomycin, penicillamine,
phenytoin, rifampin, St. John’s Wort, sucralfate,
sulfasalazine
Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20-40% as necessary.
No significant Digoxin exposure changes
Please refer to section 12 for a complete list of drugs which     
were studied but reported no significant changes on digoxin exposure.
No additional actions are required.     


Table name:
Interacting Drug
Interaction
Antacids, sucralfate, multivitamins, and other products containing multivalent cations
Moxifloxacin absorption is decreased. Administer moxifloxacin hydrochloride tablet at least 4 hours before or 8 hours after these products. (2.2, 7.1, 12.3, 17)
Warfarin
Anticoagulant effect of warfarin may be enhanced. Monitor prothrombin time/INR, watch for bleeding. (6.4, 7.2, 12.3)
Class IA and Class III antiarrhythmics:
Proarrhythmic effect may be enhanced. Avoid concomitant use. (5.3, 7.5)
Antidiabetic agents
Carefully monitor blood glucose (5.10, 7.3)


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir ) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Do not exceed 40 mg atorvastatin daily


Table name:
Table 2: Drug — Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion -the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine / Dopamine
Agonists Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥100 mg/day or equivalent); Octreotide (>100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T4 and T3 serum transport — but FT4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone > 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.


Table name:
Table 2: Clinically Significant Drug Interactions with Diclofenac
Drugs  That  Interfere  with  Hemostasis 
Clinical  Impact 
●   Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.
●   Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention 
Monitor patients with concomitant use of diclofenac sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see WARNINGS AND PRECAUTIONS (5.11)]
Aspirin 
Clinical  Impact
Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of NSAID alone [see WARNINGS AND PRECAUTIONS (5.2)]
Intervention 
Concomitant use of diclofenac sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see WARNINGS AND PRECAUTIONS (5.11)]. Diclofenac sodium is not a substitute for low dose aspirin for cardiovascular protection.
ACE  inhibitors Angiotensin  Receptor  Blockers and  Beta - Blockers 
Clinical  Impact
●   NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).
●   In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention
●  During concomitant use of diclofenac sodium and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained  ●   During concomitant use of diclofenac sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see WARNINGS AND PRECAUTIONS(5.6)] ● When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics 
Clinical  Impact
Clinical studies, as well as post-marketing observations, showed that NSAIDS reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. 
Intervention
During concomitant use of diclofenac sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see WARNINGS AND PRECAUTIONS (5.6)].
Digoxin 
Clinical  Impact
The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life digoxin. 
Intervention
During concomitant use of diclofenac sodium and digoxin, monitor serum digoxin levels. 
Lithium 
Clinical  Impact
NSAIDS have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. 
Intervention
During concomitant use of diclofenac sodium and lithium, monitor patients for signs of lithium toxicity. 
Methotrexate 
Clinical  Impact
Concomitant use of NSAIDs and methotrexate may increase the risk of methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). 
Intervention
During concomitant use of diclofenac sodium and methotrexate, monitor patients for methotrexate toxicity. 
Cyclosporine 
Clinical  Impact
Concomitant use of diclofenac sodium and cyclosporine may increase cyclosporine’s nephrotoxicity. 
Intervention
During concomitant use of diclofenac sodium and cyclosporine, monitor patients for signs or worsening renal function. 
NSAIDs  and  Salicylates 
Clinical  Impact
Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see WARNINGS AND PRECAUTIONS (5.2)]. Concomitant use of oral NSAIDs with diclofenac sodium has been evaluated in one Phase 3 controlled trial and in combination with oral diclofenac, compared to oral diclofenac alone, resulted in a higher rate of rectal hemorrhage (3% vs. less than 1%), and more frequent abnormal creatinine (12% vs. 7%), urea (20% vs. 12%) and hemoglobin (13% vs. 9%).
Intervention
The concomitant use of diclofenac with other NSAIDs or salicyclates is not recommended.
Do not use combination therapy with diclofenac sodium and an oral NSAID unless the benefit outweighs the risk and conduct periodic laboratory evaluations 
Pemetrexed 
Clinical  Impact
Concomitant use of diclofenac sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). 
Intervention
During concomitant use of diclofenac sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. 

NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration pemetrexed. 

In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. 


Table name:
AED Coadministered AED Concentration Topiramate Concentration
Phenytoin
NC or 25% increasePlasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
48% decrease


Carbamazepine (CBZ)
NC
40% decrease
CBZ epoxideIs not administered but is an active metabolite of carbamazepine.
NC
NE
Valproic acid
11% decrease
14% decrease
Phenobarbital
NC
NE
Primidone
NC
NE
Lamotrigine
NC at TPM doses up to 400 mg/day
13% decrease


Table name:
Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug Dosing Schedule Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio Change relative to reference ) Risperidone Dose Recommendation
Coadministered Drug Risperidone AUC Cmax
Enzyme (CYP2D6) Inhibitors
Fluoxetine 20 mg/day 2 or 3 mg twice daily 1.4 1.5 Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine 10 mg/day 4 mg/day 1.3 - Re-evaluate dosing. Do not exceed 8 mg/day
20 mg/day 4 mg/day 1.6 -
40 mg/day 4 mg/day 1.8 -
Enzyme (CYP3A/PgP inducers) Inducers
Carbamazepine 573 ± 168 mg/day 3 mg twice daily 0.51 0.55 Titrate dose upwards. Do not exceed twice the patient's usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine 150 mg twice daily 1 mg single dose 1.2 1.4 Dose adjustment not needed
Cimetidine 400 mg twice daily 1 mg single dose 1.1 1.3 Dose adjustment not needed
Erythromycin 500 mg four times daily 1 mg single dose 1.1 0.94 Dose adjustment not needed
Other Drugs
Amitriptyline 50 mg twice daily 3 mg twice daily 1.2 1.1 Dose adjustment not needed


Table name:
Digoxin concentrations increased > 50%
Digoxin Serum Concentration Increase Digoxin AUC Increase Recommendations
Amiodarone 70% NA Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin dose by approximately 30% to 50% and continue monitoring.
Captopril 58% 39%
Nitrendipine 57% 15%
Propafenone 35-85% NA
Quinidine 100% NA
Ranolazine 87% 88%
Ritonavir NA 86%
Verapamil 50-75% NA
Digoxin concentrations increased < 50%
Carvedilol 16% 14% Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin dose by approximately 15% to 30% and continue monitoring.
Diltiazem 20% NA
Nifedipine 45% NA
Rabeprazole 29% 19%
Telmisartan 20% NA
Digoxin concentrations increased, but magnitude is unclear
Alprazolam, Azithromycin, Clarithromycin, Cyclosporine, Diclofenac, Diphenoxylate, Epoprostenol, Erythromycin, Esomeprazole, Indomethacin, Itraconazole, Ketoconazole, Lansoprazole, Metformin, Omeprazole, Propantheline, Spironolactone, Tetracycline Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin concentrations decreased
Acarbose, Activated Charcoal, Albuterol, Antacids, Anti-cancer drugs, Cholestyramine, Colestipol, Exenatide, Kaolin-pectin, Meals High in Bran, Metoclpramide, Miglitol, Neomycin, Rifampin, Salbutamol, St. John’s Wort, Sucralfate, Sulfasalazine Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20% to 40% as necessary.
No significant Digoxin concentrations changes
Please refer to section 12.3 for a complete list of drugs which were studied but reported no significant changes on digoxin exposure. No additional actions are required.


Table name:
Table 4. Effects of Other Drugs/Substances on ENVARSUS XRa
a ENVARSUS XR dosage adjustment recommendation based on observed effect of coadministered drug on tacrolimus exposures [see Clinical Pharmacology (12.2) ], literature reports of altered tacrolimus exposures, or the other drug’s known CYP3A inhibitor/inducer status
b High dose or double strength grapefruit juice is a strong CYP3A inhibitor; low dose or single strength grapefruit juice is a moderate CYP3A inhibitor
c Strong CYP3A inhibitor/inducer, based on reported effect on exposures to tacrolimus along with supporting in vitro CYP3A inhibitor/inducer data, or based on drug-drug interaction studies with midazolam (sensitive CYP3A probe substrate)
 Drug/Substance Class or Name  Drug Interaction Effect  Recommendations
 Grapefruit or grapefruit juiceb May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see Warnings and Precautions (5.6, 5.10) ] Avoid grapefruit or grapefruit juice
 Alcohol May modify the rate of tacrolimus release Avoid alcoholic beverages
 Strong CYP3A Inducersc such as:
    Antimycobacterials (e.g.,
    rifampin, rifabutin),
    anticonvulsants (e.g., phenytoin,
    carbamazepine and
    phenobarbital), St John’s Wort
May decrease tacrolimus whole blood trough concentrations and increase the risk of rejection [see Warnings and Precautions (5.9) ] Increase ENVARSUS XR dose and monitor tacrolimus whole blood trough concentrations [see Dosage and Administration (2.3) and Clinical Pharmacology (12.2) ]
 Strong CYP3A Inhibitorsc, such as:
    Protease inhibitors (e.g.,
    nelfinavir, telaprevir, boceprevir,
    ritonavir), azole antifungals (e.g.,
    voriconazole, posaconazole,
    itraconazole, ketoconazole),
    antibiotics (e.g., clarithromycin,
    troleandomycin,
    chloramphenicol), nefazodone
May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see Warnings and Precautions (5.6, 5.9, 5.10) ] Reduce ENVARSUS XR dose (for voriconazole and posaconazole, give one-third of the original dose) and adjust dose based on tacrolimus whole blood trough concentrations [see Dosage and Administration (2.3) and Clinical Pharmacology (12.2) ]
 Mild or Moderate CYP3A
 Inhibitors, such as:
    antibiotics (e.g., erythromycin),
    calcium channel blockers (e.g.,
    verapamil, diltiazem, nifedipine,
    nicardipine), amiodarone,
    danazol, ethinyl estradiol,
    cimetidine, lansoprazole and
    omeprazole, azole antifungals
    (e.g., clotrimazole, fluconazole)
May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see Warnings and Precautions (5.6, 5.10) ] Monitor tacrolimus whole blood trough concentrations and reduce ENVARSUS XR dose if needed [see Dosage and Administration (2.3) and Clinical Pharmacology (12.2) ]
 Other drugs, such as:
    Magnesium and aluminum
     hydroxide antacids

    Metoclopramide
May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see Warnings and Precautions (5.6, 5.10) ] Monitor tacrolimus whole blood trough concentrations and reduce ENVARSUS XR dose if needed [see Dosage and Administration (2.3) and Clinical Pharmacology (12.2) ]
 Mild or Moderate CYP3A Inducers,
 such as:
    Methylprednisolone, prednisone
May decrease tacrolimus concentrations Monitor tacrolimus whole blood trough concentrations and adjust ENVARSUS XR dose if needed [see Dosage and Administration (2.3) ]


Table name:
Interacting Drug
Interaction
Warfarin
Anticoagulant effect of warfarin may be enhanced.  Monitor prothrombin time/INR, watch for bleeding. (6.4, 7.1, 12.3)
Class IA and Class III antiarrhythmics:
Proarrhythmic effect may be enhanced. Avoid concomitant use. (5.6, 7.4)
Antidiabetic agents  Carefully monitor blood glucose. (5.12, 7.2


Table name:
Interacting Drug Interaction
   Multivalent cation-containing products
   including antacids, metal cations or didanosine
   Absorption of levofloxacin is decreased when the tablet
   formulation  is taken within 2 hours of this product. (2.4, 7.1)
   Warfarin
   Effect may be enhanced. Monitor prothrombin time,
   INR, watch for bleeding (7.2)
   Antidiabetic agents
   Carefully monitor blood glucose (5.12, 7.3)


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
 Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration  Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
 Drugs that may alter T 4 and T 3 metabolism
 Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Calcium Channel Blockers Antifungals Antibiotics Glucocorticoids Other Drugs
diltiazem fluconazole azithromycin methylprednisolone allopurinol
nicardipine itraconazole clarithromycin amiodarone
verapamil ketoconazole erythromycin bromocriptine
voriconazole quinupristin/
dalfopristin
colchicine
danazol
imatinib
metoclopramide
nefazodone
oral contraceptives


Table name:
Digoxin Concentrations Increased Greater than 50%
Digoxin Serum Concentration Increase Digoxin AUC Increase Recommendations
Amiodarone 70% NA Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin dose by approximately 30% to 50% or by modifying the dosing frequency and continue monitoring.
Captopril 58% 39%
Clarithromycin NA 70%
Dronedarone NA 150%
Gentamicin 129 to 212% NA
Erythromycin 100% NA
Itraconazole 80% NA
Lapatinib NA 180%
Propafenone NA 60 to 270%
Quinidine 100% NA
Ranolazine 50% NA
Ritonavir NA 86%
Telaprevir 50% 85%
Tetracycline 100% NA
Verapamil 50 to 75% NA
Digoxin Concentrations Increased Less than 50%
Atorvastatin 22% 15% Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin dose by approximately 15% to 30% or by modifying the dosing frequency and continue monitoring.
Carvedilol 16% 14%
Conivaptan 33% 43%
Diltiazem 20% NA
Indomethacin 40% NA
Nefazodone 27% 15%
Nifedipine 45% NA
Propantheline 24% 24%
Quinine NA 33%
Rabeprazole 29% 19%
Saquinavir 27% 49%
Spironolactone 25% NA
Telmisartan 20 to 49% NA
Ticagrelor 31% 28%
Tolvaptan 30% 20%
Trimethoprim 22 to 28% NA
Digoxin Concentrations Increased, but Magnitude is Unclear
Alprazolam, Azithromycin, Cyclosporine, Diclofenac, Diphenoxylate, Epoprostenol, Esomeprazole, Ibuprofen, Ketoconazole, Lansoprazole, Metformin, Omeprazole Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin Concentrations Decreased
Acarbose, Activated Charcoal, Albuterol, Antacids, certain cancer chemotherapy or radiation therapy, Cholestyramine, Colestipol, Exenatide, Kaolin-pectin, Meals High in Bran, Metoclopramide, Miglitol, Neomycin, Penicillamine, Phenytoin, Rifampin, St. John’s Wort, Sucralfate, Sulfasalazine Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20% to 40% as necessary.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) Do not exceed 40 mg atorvastatin daily


Table name:
 AED Co-administered  AED Concentration Topiramate
Concentration
 Phenytoin  NC or 25% increasea  48% decrease
 Carbamazepine (CBZ)  NC  40% decrease
 CBZ epoxideb  NC  NE
 Valproic acid  11% decrease  14% decrease
 Phenobarbital  NC  NE
 Primidone  NC  NE
 Lamotrigine  NC at TPM doses up to 400 mg/day  13% decrease
a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
b = Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated


Table name:
AED Coadministered AED Concentration Topiramate Concentration
Phenytoin NC or 25% increasea 48% decrease
Carbamazepine (CBZ) NC 40% decrease
CBZ epoxideb NC NE
Valproic acid 11% decrease 14% decrease
Phenobarbital NC NE
Primidone NC NE
Lamotrigine NC at TPM doses up to 400 mg/day 13% decrease


Table name:
AED Coadministered AED Concentration Topiramate Concentration
Phenytoin NC or 25% increasePlasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. 48% decrease
Carbamazepine (CBZ) NC 40% decrease
CBZ epoxideIs not administered but is an active metabolite of carbamazepine. NC NE
Valproic acid 11% decrease 14% decrease
Phenobarbital NC NE
Primidone NC NE
Lamotrigine NC at TPM doses up to 400 mg/day 13% decrease
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated.


Table name:
Table 8: Clinically Significant Drug Interactions with Clarithromycin
Drugs That Are Affected By Clarithromycin
Drug(s) with Pharmacokinetics Affected by Clarithromycin
Recommendation
Comments
Antiarrhythmics:
 
Disopyramide
Quinidine
Dofetilide
Amiodarone
Sotalol
Procainamide
 
 
 
 
Digoxin
 
 
Not Recommended
 
 
 
 
 
 
 
 
Use With Caution
 
 
Disopyramide, Quinidine: There have been postmarketing reports of torsades de pointes occurring with concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QTc prolongation during coadministration of clarithromycin with these drugs [see Warnings and Precautions (5.3)].
 
Serum concentrations of these medications should also be monitored. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with disopyramide and quinidine.
 
There have been postmarketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide. Therefore, blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide.
 
Digoxin: Digoxin is a substrate for P-glycoprotein (Pgp) and clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are co-administered, inhibition of Pgp by clarithromycin may lead to increased exposure of digoxin. Elevated digoxin serum concentrations in patients receiving clarithromycin and digoxin concomitantly have been reported in postmarketing surveillance. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Monitoring of serum digoxin concentrations should be considered, especially for patients with digoxin concentrations in the upper therapeutic range.
Oral Anticoagulants:
 
Warfarin
 
 
Use With Caution
 
 
Oral anticoagulants: Spontaneous reports in the postmarketing period suggest that concomitant administration of clarithromycin and oral anticoagulants may potentiate the effects of the oral anticoagulants. Prothrombin times should be carefully monitored while patients are receiving clarithromycin and oral anticoagulants simultaneously [see Warnings and Precautions (5.4)].
Antiepileptics:
 
Carbamazepine
 
 
Use With Caution
 
 
Carbamazepine: Concomitant administration of single doses of clarithromycin and carbamazepine has been shown to result in increased plasma concentrations of carbamazepine. Blood level monitoring of carbamazepine may be considered. Increased serum concentrations of carbamazepine were observed in clinical trials with clarithromycin. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with carbamazepine.
Antifungals:
 
Itraconazole
 
 
 

Fluconazole
 
 
Use With Caution
 
 
 

No Dose Adjustment
 
 
Itraconazole: Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when administered concomitantly (see also Itraconazole under “Drugs That Affect Clarithromycin” in the table below). Clarithromycin may increase the plasma concentrations of itraconazole. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions.
 
Fluconazole:  [see Pharmacokinetics (12.3)]
 

Anti-Gout Agents:
 
Colchicine (in patients with renal or hepatic impairment)
 
Colchicine (in patients with normal renal and hepatic function)
 
 
Contraindicated
 
 
Use With Caution
 
 
Colchicine: Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. The dose of colchicine should be reduced when co-administered with clarithromycin in patients with normal renal and hepatic function [see Contraindications (4.4) and Warnings and Precautions (5.4)].
Antipsychotics:
 
Pimozide
 
Quetiapine
 
 
Contraindicated
 
 
Pimozide:  [See Contraindications (4.2)]

Quetiapine: Quetiapine is a substrate for CYP3A4, which is inhibited by clarithromycin. Co-administration with clarithromycin could result in increased quetiapine exposure and possible quetiapine related toxicities. There have been postmarketing reports of somnolence, orthostatic hypotension, altered state of consciousness, neuroleptic malignant syndrome, and QT prolongation during concomitant administration. Refer to quetiapine prescribing information for recommendations on dose reduction if co-administered with CYP3A4 inhibitors such as clarithromycin.
Antispasmodics:
 
Tolterodine (patients deficient in CYP2D6 activity)
 
 
Use With Caution
 
 
Tolterodine: The primary route of metabolism for tolterodine is via. CYP2D6. However, in a subset of the population devoid of CYP2D6, the identified pathway of metabolism is via. CYP3A. In this population subset, inhibition of CYP3A results in significantly higher serum concentrations of tolterodine. Tolterodine 1 mg twice daily is recommended in patients deficient in CYP2D6 activity (poor metabolizers) when co-administered with clarithromycin.
Antivirals:
 
Atazanavir
 

Saquinavir (in patients with decreased renal function)
 
Ritonavir
Etravirine
 
Maraviroc
 

Boceprevir (in patients with normal renal function)
 
Didanosine
 
Zidovudine


 
 
Use With Caution
 
 
 
 
 
 
 
 
 
 

No Dose Adjustment
 
 
Atazanavir: Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction (see Atazanavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)].
 
Saquinavir: Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A and there is evidence of a bi-directional drug interaction (see Saquinavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)].
 
Ritonavir, Etravirine: (see Ritonavir and Etravirine under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)].
 

Maraviroc
: Clarithromycin may result in increases in maraviroc exposures by inhibition of CYP3A metabolism. See Selzentry® prescribing information for dose recommendation when given with strong CYP3A inhibitors such as clarithromycin.
 
Boceprevir: Both clarithromycin and boceprevir are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when co-administered. No dose adjustments are necessary for patients with normal renal function (see Victrelis® prescribing information).
 


Zidovudine:
Simultaneous oral administration of clarithromycin immediate-release tablets and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine concentrations. Administration of clarithromycin and zidovudine should be separated by at least two hours [see Pharmacokinetics (12.3)].
Calcium Channel Blockers:
 
Verapamil
 

Amlodipine
Diltiazem
 
Nifedipine
 
 
Use With Caution
 
 
Verapamil: Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent verapamil, [see Warnings and Precautions (5.4)].
 
Amlodipine, Diltiazem: [See Warnings and Precautions (5.4)]

 
Nifedipine: Nifedipine is a substrate for CYP3A. Clarithromycin and other macrolides are known to inhibit CYP3A. There is potential of CYP3A-mediated interaction between nifedipine and clarithromycin. Hypotension and peripheral edema were observed when clarithromycin was taken concomitantly with nifedipine [see Warnings and Precautions (5.4)].
Ergot Alkaloids:
 
Ergotamine
Dihydroergotamine
 
 
Contraindicated
 
 
Ergotamine, Dihydroergotamine: Postmarketing reports indicate that coadministration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system [see Contraindications (4.6)].
Gastroprokinetic  Agents:
 
Cisapride
 
 
Contraindicated
 
 
Cisapride: [See Contraindications (4.2)]
HMG-CoA Reductase Inhibitors:
 
Lovastatin
Simvastatin
 
Atorvastatin
Pravastatin
 
Fluvastatin

 
 
Contraindicated
 
 
Use With Caution
 
No Dose Adjustment
 
 
Lovastatin, Simvastatin, Atorvastatin, Pravastatin, Fluvastatin:  [See Contraindications (4.5) and Warnings and Precautions (5.4)]
Hypoglycemic Agents:
 
Nateglinide
Pioglitazone
Repaglinide
Rosiglitazone
 
Insulin

 
 
Use With Caution
 
 
Nateglinide, Pioglitazone, Repaglinide, Rosiglitazone: [See Warnings and Precautions (5.4) and Adverse Reactions (6.2)]
 



Insulin: [See Warnings and Precautions (5.4) and Adverse Reactions (6.2)]
Immunosuppressants:
 
Cyclosporine
 
Tacrolimus
 
 
Use With Caution
 
 
Cyclosporine: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with cyclosporine.
 
Tacrolimus: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with tacrolimus.
Phosphodiesterase inhibitors:
 
Sildenafil
Tadalafil
Vardenafil
 
 
 
Use With Caution
 
 
 
Sildenafil, Tadalafil, Vardenafil: Each of these phosphodiesterase inhibitors is primarily metabolized by CYP3A, and CYP3A will be inhibited by concomitant administration of clarithromycin. Co-administration of clarithromycin with sildenafil, tadalafil, or vardenafil will result in increased exposure of these phosphodiesterase inhibitors. Co-administration of these phosphodiesterase inhibitors with clarithromycin is not recommended. Increased systemic exposure of these drugs may occur with clarithromycin; reduction of dosage for phosphodiesterase inhibitors should be considered (see their respective prescribing information).
Proton Pump Inhibitors:
 
Omeprazole
 
 
No Dose Adjustment
 
 
Omeprazole: The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when coadministered with clarithromycin as a result of increased omeprazole exposures [see Pharmacokinetics (12.3)] (see also Omeprazole under “Drugs That Affect Clarithromycin” in the table below).
Xanthine Derivatives:
 
Theophylline
 
 
Use With Caution
 
 
Theophylline: Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serum theophylline concentrations [see Pharmacokinetics (12.3)]. Monitoring of serum theophylline concentrations should be considered for patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range.
Triazolobenzodiazepines and Other Related Benzodiazepines:
 
Midazolam
 
 
Alprazolam
Triazolam
 
 
 
 
 
Temazepam
Nitrazepam
Lorazepam
 
 
 
Use With Caution
 
 
 
 
 
 
 
 
 
No Dose Adjustment
 
 
 
Midazolam: When oral midazolam is co-administered with clarithromycin, dose adjustments may be necessary and possible prolongation and intensity of effect should be anticipated [see Warnings and Precautions (5.4) and Pharmacokinetics (12.3)].
 
Triazolam, Alprazolam: Caution and appropriate dose adjustments should be considered when triazolam or alprazolam is co-administered with clarithromycin. There have been postmarketing reports of drug interactions and central nervous system (CNS) effects (e.g., somnolence and confusion) with the concomitant use of clarithromycin and triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested.
 
In postmarketing experience, erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines.
 
Temazepam, Nitrazepam, Lorazepam: For benzodiazepines which are not metabolized by CYP3A (e.g., temazepam, nitrazepam, lorazepam), a clinically important interaction with clarithromycin is unlikely.
Cytochrome P450 Inducers:
 
Rifabutin
 
 
Use With Caution
 
 
Rifabutin: Concomitant administration of rifabutin and clarithromycin resulted in an increase in rifabutin, and decrease in clarithromycin serum levels together with an increased risk of uveitis (see Rifabutin under “Drugs That Affect Clarithromycin” in the table below).
Other Drugs
Metabolized by CYP3A:
 
Alfentanil
Bromocriptine
Cilostazol
Methylprednisole Vinblastine
Phenobarbital
St. John’s Wort
 
 
 
Use With Caution
 
 
 
There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with alfentanil, methylprednisolone, cilostazol, bromocriptine, vinblastine, phenobarbital, and St. John’s Wort.
Other Drugs Metabolized by CYP450 Isoforms Other than CYP3A:
 
Hexobarbital
Phenytoin
Valproate
 
 
 
 
Use With Caution
 
 
 
 
There have been postmarketing reports of interactions of clarithromycin with drugs not thought to be metabolized by CYP3A, including hexobarbital, phenytoin, and valproate.


                                                                                                                                       Drugs that Affect Clarithromycin
Drug(s) that Affect the Pharmacokinetics of Clarithromycin

Recommendation

                                                                                     Comments
Antifungals:
 
Itraconazole
 
 
Use With Caution
 
 
Itraconazole: Itraconazole may increase the plasma concentrations of clarithromycin. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions (see also Itraconazole under “Drugs That Are Affected By Clarithromycin” in the table above).
Antivirals:
 
Atazanavir
 
 
 
 
 
 
Ritonavir (in patients with decreased renal function)
 
 
Saquinavir (in patients with decreased renal function)
 
Etravirine
 
 
 
 
Saquinavir (in patients with normal renal function) Ritonavir (in patients with normal renal function)
 
 
Use With Caution
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
No Dose Adjustment
 
 
Atazanavir: When clarithromycin is co-administered with atazanavir, the dose of clarithromycin should be decreased by 50% [see Clinical Pharmacology (12.3)].
 
Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with atazanavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium complex. Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.
 
Ritonavir: Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with ritonavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium [see Pharmacokinetics (12.3)].
 
Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.
 
Saquinavir: When saquinavir is co-administered with ritonavir, consideration should be given to the potential effects of ritonavir on clarithromycin (refer to ritonavir above) [see Pharmacokinetics (12.3)].
 
Etravirine: Clarithromycin exposure was decreased by etravirine; however, concentrations of the active metabolite, 14-OH-clarithromycin, were increased. Because 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered; therefore alternatives to clarithromycin should be considered for the treatment of MAC.
Proton Pump Inhibitors:
 
Omeprazole
 
 
Use With Caution
 
 
Omeprazole: Clarithromycin concentrations in the gastric tissue and mucus were also increased by concomitant administration of omeprazole [see Pharmacokinetics (12.3)].
Miscellaneous Cytochrome P450 Inducers:
 
Efavirenz
Nevirapine
Rifampicin
Rifabutin
Rifapentine
 
 
 
Use With Caution
 
 
 
Inducers of CYP3A enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine will increase the metabolism of clarithromycin, thus decreasing plasma concentrations of clarithromycin, while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. Alternative antibacterial treatment should be considered when treating patients receiving inducers of CYP3A. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with rifabutin (see Rifabutin under “Drugs That Are Affected By Clarithromycin” in the table above).


Table name:
Figure 1: Effect of interacting drugs on the pharmacokinetics of venlafaxine and active metabolite O-desmethylvenlafaxine (ODV).


Table name:
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor
(boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Table 7. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class: Drug Name Effect on Concentration of Amprenavir or Concomitant Drug Clinical Comment
HCV/HIV-Antiviral Agents
HCV protease inhibitor: Boceprevir LEXIVA: ↓Amprenavir (predicted) ↔ or ↓Boceprevir (predicted) LEXIVA/ritonavir: ↓Amprenavir (predicted) ↓Boceprevir (predicted) Coadministration of LEXIVA or LEXIVA/ritonavir and boceprevir is not recommended.
HCV protease inhibitor: Simeprevir LEXIVA: ↔Amprenavir (predicted) ↑ or ↓Simeprevir (predicted) LEXIVA/ritonavir: ↔Amprenavir (predicted) ↑Simeprevir (predicted) Coadministration of LEXIVA or LEXIVA/ritonavir and simeprevir is not recommended.
HCV protease inhibitor: Paritaprevir (coformulated with ritonavir and ombitasvir and coadministered with dasabuvir) LEXIVA: ↑Amprenavir (predicted) ↑ or ↔Paritaprevir (predicted) LEXIVA/ritonavir: ↑ or ↔Amprenavir (predicted) ↑Paritaprevir (predicted) Appropriate doses of the combinations with respect to safety and efficacy have not been established. LEXIVA 1400 mg once daily may be considered when coadministered with paritaprevir/ritonavir/ombitasvir/ dasabuvir. Coadministration of LEXIVA/ritonavir and paritaprevir/ritonavir/ombitasvir/ dasabuvir is not recommended.
Non-nucleoside reverse transcriptase inhibitor: Efavirenz a LEXIVA: ↓Amprenavir LEXIVA/ritonavir: ↓Amprenavir Appropriate doses of the combinations with respect to safety and efficacy have not been established. An additional 100 mg/day (300 mg total) of ritonavir is recommended when efavirenz is administered with LEXIVA/ritonavir once daily. No change in the ritonavir dose is required when efavirenz is administered with LEXIVA plus ritonavir twice daily.
Non-nucleoside reverse transcriptase inhibitor: Nevirapine a LEXIVA: ↓Amprenavir ↑Nevirapine LEXIVA/ritonavir: ↓Amprenavir ↑Nevirapine Coadministration of nevirapine and LEXIVA without ritonavir is not recommended. No dosage adjustment required when nevirapine is administered with LEXIVA/ritonavir twice daily. The combination of nevirapine administered with LEXIVA/ritonavir once-daily regimen has not been studied.
HIV protease inhibitor: Atazanavir a LEXIVA: Interaction has not been evaluated. LEXIVA/ritonavir: ↓Atazanavir ↔Amprenavir Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV protease inhibitors: Indinavir a, nelfinavir a LEXIVA: ↑Amprenavir Effect on indinavir and nelfinavir is not well established. LEXIVA/ritonavir: Interaction has not been evaluated. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV protease inhibitors: Lopinavir/ritonavir a ↓Amprenavir ↓Lopinavir An increased rate of adverse events has been observed. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV protease inhibitor: Saquinavir a LEXIVA: ↓Amprenavir Effect on saquinavir is not well established. LEXIVA/ritonavir: Interaction has not been evaluated. Appropriate doses of the combination with respect to safety and efficacy have not been established.
HIV integrase inhibitor: Raltegravir a LEXIVA: ↓Amprenavir ↓Raltegravir LEXIVA/ritonavir: ↓Amprenavir ↓Raltegravir Appropriate doses of the combination with respect to safety and efficacy have not been established.
HIV integrase inhibitor: Dolutegravir a LEXIVA/ritonavir: ↓Dolutegravir The recommended dose of dolutegravir is 50 mg twice daily when coadministered with LEXIVA/ritonavir. Use an alternative combination where possible in patients with known or suspected integrase inhibitor resistance.
HIV CCR5 co-receptor antagonist: Maraviroc a LEXIVA/ritonavir: ↓Amprenavir ↑Maraviroc No dosage adjustment required for LEXIVA/ritonavir. The recommended dose of maraviroc is 150 mg twice daily when coadministered with LEXIVA/ritonavir. LEXIVA should be given with ritonavir when coadministered with maraviroc.
Other Agents
Antiarrhythmics: Amiodarone, lidocaine (systemic), and quinidine ↑Antiarrhythmics Use with caution. Increased exposure may be associated with life-threatening reactions such as cardiac arrhythmias. Therapeutic concentration monitoring, if available, is recommended for antiarrhythmics.
Anticoagulant: Warfarin Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants: Carbamazepine, phenobarbital, phenytoin Phenytoin a LEXIVA: ↓Amprenavir LEXIVA/ritonavir: ↑Amprenavir ↓Phenytoin Use with caution. LEXIVA may be less effective due to decreased amprenavir plasma concentrations in patients taking these agents concomitantly. Plasma phenytoin concentrations should be monitored and phenytoin dose should be increased as appropriate. No change in LEXIVA/ritonavir dose is recommended.
Antidepressant: Paroxetine, trazodone ↓Paroxetine ↑Trazodone Any paroxetine dose adjustment should be guided by clinical effect (tolerability and efficacy). Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as LEXIVA, the combination should be used with caution and a lower dose of trazodone should be considered.
Antifungals: Ketoconazole a, itraconazole ↑Ketoconazole ↑Itraconazole Increase monitoring for adverse events. LEXIVA: Dose reduction of ketoconazole or itraconazole may be needed for patients receiving more than 400 mg ketoconazole or itraconazole per day. LEXIVA/ritonavir: High doses of ketoconazole or itraconazole (greater than 200 mg/day) are not recommended.
Anti-gout: Colchicine ↑Colchicine Patients with renal or hepatic impairment should not be given colchicine with LEXIVA/ritonavir. LEXIVA/ritonavir and coadministration of colchicine: Treatment of gout flares: 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.
If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.
Treatment of familial Mediterranean fever (FMF): Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). LEXIVA and coadministration of colchicine: Treatment of gout flares: 1.2 mg (2 tablets) x 1 dose. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg twice a day or 0.6 mg once a day.
If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once a day.
Treatment of FMF: Maximum daily dose of 1.2 mg (may be given as 0.6 mg twice a day).
Antimycobacterial: Rifabutin a ↑Rifabutin and rifabutin metabolite A complete blood count should be performed weekly and as clinically indicated to monitor for neutropenia. LEXIVA: A dosage reduction of rifabutin by at least half the recommended dose is required. LEXIVA/ritonavir: Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (a maximum dose of 150 mg every other day or 3 times per week).
Antipsychotics: Quetiapine LEXIVA/ritonavir: ↑Quetiapine Initiation of LEXIVA with ritonavir in patients taking quetiapine: Consider alternative antiretroviral therapy to avoid increases in quetiapine drug exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring. Initiation of quetiapine in patients taking LEXIVA with ritonavir: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.
Lurasidone ↑Lurasidone LEXIVA: If coadministration is necessary, reduce the lurasidone dose. Refer to the lurasidone prescribing information for concomitant use with moderate CYP3A4 inhibitors. LEXIVA/ritonavir: Use of lurasidone is contraindicated.
Benzodiazepines: Alprazolam, clorazepate, diazepam, flurazepam ↑Benzodiazepines Clinical significance is unknown. A decrease in benzodiazepine dose may be needed.
Calcium channel blockers: Diltiazem, felodipine, nifedipine, nicardipine, nimodipine, verapamil, amlodipine, nisoldipine, isradipine ↑Calcium channel blockers Use with caution. Clinical monitoring of patients is recommended.
Corticosteroid: Dexamethasone ↓Amprenavir Use with caution. LEXIVA may be less effective due to decreased amprenavir plasma concentrations.
Endothelin-receptor antagonists: Bosentan ↑Bosentan Coadministration of bosentan in patients on LEXIVA: In patients who have been receiving LEXIVA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Coadministration of LEXIVA in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of LEXIVA. After at least 10 days following the initiation of LEXIVA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Histamine H 2-receptor antagonists: Cimetidine, famotidine, nizatidine, ranitidine a LEXIVA: ↓Amprenavir LEXIVA/ritonavir: Interaction not evaluated Use with caution. LEXIVA may be less effective due to decreased amprenavir plasma concentrations.
HMG-CoA reductase inhibitors: Atorvastatin a ↑Atorvastatin Titrate atorvastatin dose carefully and use the lowest necessary dose; do not exceed atorvastatin 20 mg/day.
Immunosuppressants: Cyclosporine, tacrolimus, sirolimus ↑Immunosuppressants Therapeutic concentration monitoring is recommended for immunosuppressant agents.
Inhaled beta-agonist: Salmeterol ↑Salmeterol Concurrent administration of salmeterol with LEXIVA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.
Inhaled/nasal steroid: Fluticasone LEXIVA: ↑Fluticasone LEXIVA/ritonavir: ↑Fluticasone Use with caution. Consider alternatives to fluticasone, particularly for long-term use. May result in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression have been reported during postmarketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone. Coadministration of fluticasone and LEXIVA/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.
Narcotic analgesic: Methadone ↓Methadone Data suggest that the interaction is not clinically relevant; however, patients should be monitored for opiate withdrawal symptoms.
Oral contraceptives: Ethinyl estradiol/norethindrone a LEXIVA: ↓Amprenavir ↓Ethinyl estradiol LEXIVA/ritonavir: ↓Ethinyl estradiol Alternative methods of non-hormonal contraception are recommended. May lead to loss of virologic response. a Increased risk of transaminase elevations. No data are available on the use of LEXIVA/ritonavir with other hormonal therapies, such as hormone replacement therapy (HRT) for postmenopausal women.
PDE5 inhibitors: Sildenafil, tadalafil, vardenafil ↑Sildenafil ↑Tadalafil ↑Vardenafil May result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Use of sildenafil (REVATIO) is contraindicated when used for the treatment of PAH [see Contraindications (4)]. The following dose adjustments are recommended for use of tadalafil (ADCIRCA ®) with LEXIVA: Coadministration of ADCIRCA in patients on LEXIVA: In patients receiving LEXIVA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Coadministration of LEXIVA in patients on ADCIRCA: Avoid use of ADCIRCA during the initiation of LEXIVA. Stop ADCIRCA at least 24 hours prior to starting LEXIVA. After at least one week following the initiation of LEXIVA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: LEXIVA: Sildenafil: 25 mg every 48 hours. Tadalafil: no more than 10 mg every 72 hours. Vardenafil: no more than 2.5 mg every 24 hours. LEXIVA/ritonavir: Sildenafil: 25 mg every 48 hours. Tadalafil: no more than 10 mg every 72 hours. Vardenafil: no more than 2.5 mg every 72 hours. Use with increased monitoring for adverse events.
Proton pump inhibitors: Esomeprazole a, lansoprazole, omeprazole, pantoprazole, rabeprazole LEXIVA: ↔Amprenavir ↑Esomeprazole LEXIVA/ritonavir: ↔Amprenavir ↔Esomeprazole Proton pump inhibitors can be administered at the same time as a dose of LEXIVA with no change in plasma amprenavir concentrations.
Tricyclic antidepressants: Amitriptyline, imipramine ↑Tricyclics Therapeutic concentration monitoring is recommended for tricyclic antidepressants.


Table name:
Table 18 Summary of Effect of Co-administered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
  Co-administered Drug   Dosing Schedule   Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*)   Risperidone Dose Recommendation
    Co-administered Drug   Risperidone   AUC   Cmax  
 Enzyme (CYP2D6)Inhibitors          
 Fluoxetine  20 mg/day  2 or 3 mg twice daily  1.4  1.5  Re-evaluate dosing. Do not exceed 8 mg/day
 Paroxetine  10 mg/day  4 mg/day  1.3  -  
   20 mg/day  4 mg/day  1.6  -  
   40 mg/day  4 mg/day  1.8  -  Re-evaluate dosing. Do not exceed 8 mg/day
 Enzyme (CYP3A/PgP inducers)Inducers          
 Carbamazepine  573 ± 168 mg/day  3 mg twice daily  0.51  0.55  Titrate dose upwards. Do not exceed twice the patient’s usual dose
 Enzyme (CYP3A)Inhibitors          
 Ranitidine  150 mg twice daily  1 mg single dose  1.2  1.4  Dose adjustment not needed
 Cimetidine  400 mg twice daily  1 mg single dose  1.1  1.3  Dose adjustment not needed
 Erythromycin  500 mg four times daily  1 mg single dose  1.1  0.94  Dose adjustment not needed
           
 Other Drugs          
 Amitriptyline  50 mg twice daily  3 mg twice daily  1.2  1.1  Dose adjustment not needed


Table name:
a Should be administered at least 4 hours prior to WELCHOL
b No significant alteration of warfarin drug levels with warfarin and WELCHOL coadministration in an in vivo study which did not evaluate warfarin pharmacodynamics (INR). [See Post-marketing Experience (6.2)]
c Cyclosporine levels should be monitored and, based on theoretical grounds, cyclosporine should be administered at least 4 hours prior to WELCHOL.
d Patients receiving concomitant metformin ER and colesevelam should be monitored for clinical response as is usual for the use of anti-diabetes drugs.
Table 4 Drugs Tested in In Vitro Binding or In Vivo Drug Interaction Testing or With Post-Marketing Reports
Drugs with a known interaction with colesevelam:
Decrease in exposure of coadministered drug
cyclosporinec, glimepiridea, glipizidea, glyburidea,
levothyroxinea, olmesartan medoxomila, and oral
contraceptives containing ethinyl estradiol and
norethindronea
Drugs with a known interaction with colesevelam:
Increase in exposure of coadministered drug
metformin extended release (ER)d
Drug(s) with postmarketing reports consistent with
potential drug-drug interactions when
coadministered with WELCHOL
phenytoina, warfarinb
Drugs that do not interact with colesevelam based
on in vitro or in vivo testing
aspirin, atenolol, cephalexin, ciprofloxacin,
digoxin, enalapril, fenofibrate, lovastatin,
metformin, metoprolol, phenytoina, pioglitazone,
rosiglitazone, quinidine, repaglinide, sitagliptin,
valproic acid, verapamil, warfarinb


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( , , , ) 2.6 5.1 7 12.3
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.7, 5.1, 7.1, 7.2, 7.3, 7.6, 7.8)
Interacting Agents Prescribing Recommendations
Itraconazole,
ketoconazole,
erythromycin,
clarithromycin,
telithromycin, HIV protease inhibitors,
nefazodone,
fibrates
Avoid VYTORIN
Cyclosporine, danazol Do not exceed 10/10 mg VYTORIN daily
Amiodarone, verapamil Do not exceed 10/20 mg VYTORIN daily
Diltiazem Do not exceed 10/40 mg VYTORIN daily
Grapefruit juice Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3,  12.3)
* For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Interacting Agents
Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol
Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone
Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine
Do not exceed 20 mg simvastatin daily
Lomitapide
For patients with HoFH, do not exceed 20 mg simvastatin daily*
Grapefruit juice
Avoid grapefruit juice


Table name:
Table 4: Established and Other Potentially Significant Drug Interactions: Alteration in CERDELGA Dosage May Be Recommended Based on Predicted Interaction in PMs
CYP450 Inhibitors Recommended CERDELGA Dosage for PMs
Strong CYP3A inhibitors
e.g., ketoconazole
Contraindicated
Moderate CYP3A inhibitors
e.g., fluconazole
Not recommended
Weak CYP3A inhibitors
e.g., ranitidine
Not recommended


Table name:
Interacting DrugInteracting Drug InteractionInteraction
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products ( 2.4, 7.1)
Warfarin
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( 7.2)
Antidiabetic agents
Carefully monitor blood glucose ( 5.12, 7.3)


Table name: Pimozide Clinical ImpactIncreased pimozide exposureInterventionaprepitant is contraindicated [see CONTRAINDICATIONS (4)]. Benzodiazepines Clinical ImpactIncreased exposure to midazolam or other benzodiazepines metabolized via CYP3A4 (alprazolam, triazolam) may increase the risk of adverse reactions [see CLINICAL PHARMACOLOGY (12.3)].Intervention125-mg/80-mg/80-mg aprepitant regimen • Monitor for benzodiazepine-related adverse reactions. • Depending on the clinical situation (e.g., elderly patients) and degree of monitoring available, reduce the dose of intravenous midazolam Single 40 mg dose of aprepitant • No dosage adjustment of the benzodiazepine needed Dexamethasone Clinical ImpactIncreased dexamethasone exposure [see CLINICAL PHARMACOLOGY (12.3)].Intervention125-mg/80-mg/80-mg aprepitant regimen • Reduce the dose of oral dexamethasone by approximately 50% [see DOSAGE AND ADMINISTRATION (2.1)]. Single 40 mg dose of aprepitant • No dosage adjustment of oral dexamethasone needed Methylprednisolone Clinical ImpactIncreased methylprednisolone exposure [see CLINICAL PHARMACOLOGY (12.3)].Intervention125-mg/80-mg/80-mg aprepitant regimen • Reduce the dose of intravenous methylprednisolone by approximately 25% • Reduce the dose of oral methylprednisolone by approximately 50% Single 40 mg dose of aprepitant • No dosage adjustment of methylprednisolone needed Chemotherapeutic agents that are metabolized by CYP3A4 Clinical ImpactIncreased exposure of the chemotherapeutic agent may increase the risk of adverse reactions [see CLINICAL PHARMACOLOGY (12.3)].InterventionVinblastine, vincristine, or ifosfamide or other chemotherapeutic agents • Monitor for chemotherapeutic-related adverse reactions. Etoposide, vinorelbine, paclitaxel, and docetaxel • No dosage adjustment needed. Hormonal Contraceptives Clinical ImpactDecreased hormonal exposure during administration of and for 28 days after administration of the last dose of aprepitant [see CLINICAL PHARMACOLOGY (12.3)].InterventionAlternative or back-up methods of contraception should be used during treatment with aprepitant and for 1 month following the last dose of aprepitantExamplesbirth control pills, skin patches, implants, and certain IUDsCYP2C9 Substrates Warfarin Clinical ImpactDecreased warfarin exposure and prolongation of prothrombin time (INR) [see CLINICAL PHARMACOLOGY (12.3)].InterventionIn patients on chronic warfarin therapy, monitor the prothrombin time (INR) in the 2-week period, particularly at 7 to 10 days, following initiation of the 125-mg/80-mg/80-mg aprepitant regimen with each chemotherapy cycle, or following administration of a single 40-mg dose of aprepitant.Other 5-HT3 Antagonists Clinical ImpactNo change in the exposure of the 5-HT3 antagonist [see CLINICAL PHARMACOLOGY (12.3)].InterventionNo dosage adjustment neededExamplesondansetron, granisetron, dolasetron
CYP3A4 Substrates
 
 
 
 
 
 
 
 
 
       
 
 
 
 
       
 
 
 
 
         
 
 
 
 
       
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 


Table name:
Interacting Agents  Prescribing Recommendations  
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors,boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily 
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily 
Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin daily*
Grapefruit juice  Avoid grapefruit juice 
 *For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.


Table name:
  Factors   Dosage Adjustments for Aripiprazole
 Known CYP2D6 Poor Metabolizers  Administer half of usual dose
 Known CYP2D6 Poor Metabolizersand strong CYP3A4 inhibitors  Administer a quarter of usual dose
 Strong CYP2D6 or CYP3A4 inhibitors  Administer half of usual dose
 Strong CYP2D6 and CYP3A4inhibitors  Administer a quarter of usual dose
 Strong CYP3A4 inducers  Double usual dose over 1 to 2 weeks


Table name:
CYP2C19 or CYP3A4 Inducers
Clinical Impact: Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology (12.3)].
Intervention: St. John’s Wort, rifampin: Avoid concomitant use with omeprazole [see Warnings and Precautions (5.9)].

Ritonavir-containing products: see prescribing information for specific drugs.
CYP2C19 or CYP3A4 Inhibitors
Clinical Impact: Increased exposure of omeprazole [see Clinical Pharmacology (12.3)].
  Intervention: Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered.

See prescribing information for voriconazole.


Table name:
Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Diluent Storage
Room Temp.
(25°C)
Refrigerated
(4°C)
Sterile Water 2 days 10 days
0.9% Sodium Chloride Solution 2 days 10 days
5% Dextrose Solution 2 days 10 days
10% Dextrose Solution 2 days 10 days
5% Dextrose + 0.9% Sodium Chloride SolutionData available for 10 to 40 mg/mL concentrations in this diluent in PVC containers only. 2 days Incompatible
5% Dextrose + 0.45% Sodium Chloride Solution 2 days Incompatible


Table name:
Table 10 Drugs That Should Not Be Coadministered With VIRACEPT
Drug Class: Drug Name Clinical Comment
Antiarrhythmics:
amiodarone, quinidine
CONTRAINDICATED due to potential for serious and/or life threatening reactions such as cardiac arrhythmias.
Antimycobacterial:
rifampin
May lead to loss of virologic response and possible resistance to VIRACEPT or other coadministered antiretroviral agents.
Ergot Derivatives:
dihydroergotamine, ergonovine, ergotamine, methylergonovine
CONTRAINDICATED due to potential for serious and/or life threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
Herbal Products:
St. John's wort (hypericum perforatum)
May lead to loss of virologic response and possible resistance to VIRACEPT or other coadministered antiretroviral agents.
HMG-CoA Reductase Inhibitors:
lovastatin, simvastatin
Potential for serious reactions such as risk of myopathy including rhabdomyolysis.
Neuroleptic:
pimozide
CONTRAINDICATED due to potential for serious and/or life threatening reactions such as cardiac arrhythmias.
Proton Pump Inhibitors Omeprazole decreases the plasma concentrations of nelfinavir. Concomitant use of proton pump inhibitors and VIRACEPT may lead to a loss of virologic response and development of resistance.
Sedative/Hypnotics:
midazolam, triazolam
CONTRAINDICATED due to potential for serious and/or life threatening reactions such as prolonged or increased sedation or respiratory depression.


Table name:
Interacting DrugInteracting Drug InteractionInteraction
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products.
Warfarin
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents
Carefully monitor blood glucose (5.11, 7.3)


Table name:
Table 1: Clinically Significant Drug Interactions with Naproxen
Drugs That Interfere with Hemostasis
Clinical Impact: Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of naproxen tablets with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: Concomitant use of naproxen tablets and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen tablets are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: During concomitant use of naproxen tablets and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of naproxen tablets and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention During concomitant use of naproxen tablets with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact: The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of naproxen tablets and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen tablets and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of naproxen tablets and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of naproxen tablets and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of naproxen tablets and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of naproxen tablets and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of naproxen tablets and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact: Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention: Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen tablets are not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen tablets are not recommended.
Cholestyramine
Clinical Impact: Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention: Concomitant administration of cholestyramine with naproxen tablets are not recommended.
Probenecid
Clinical Impact: Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention: Patients simultaneously receiving naproxen tablets and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact: Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention: Patients simultaneously receiving naproxen tablets and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.


Table name:
Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast,
moricizine,
omeprazole, phenobarbital, phenytoin,
cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir,
aprepitant,
bosentan,
carbamazepine, efavirenz,
etravirine,
modafinil, nafcillin,
phenytoin,
pioglitazone, prednisone,
rifampin,
rufinamide


Table name:
Factors Dosage Adjustments for Aripiprazole
Known CYP2D6 Poor Metabolizers Administer half of usual dose
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors Administer half of usual dose
Strong CYP2D6 and CYP3A4 inhibitors Administer a quarter of usual dose
Strong CYP3A4 inducers Double usual dose over 1 to 2 weeks


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
 Concomitant Drug  Effect on Concentration of Lamotrigine or Concomitant Drug  Clinical Comment
 Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel  ↓ lamotrigine  Decreased lamotrigine levels approximately 50%.
 ↓ levonorgestrel  Decrease in levonorgestrel component by 19%.
 Carbamazepine (CBZ) and CBZ epoxide  ↓ lamotrigine  Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
 ? CBZ epoxide  May increase CBZ epoxide levels.
 Phenobarbital/Primidone  ↓ lamotrigine  Decreased lamotrigine concentration approximately 40%.
 Phenytoin (PHT)  ↓ lamotrigine  Decreased lamotrigine concentration approximately 40%.
 Rifampin  ↓ lamotrigine  Decreased lamotrigine AUC approximately 40%.
 Valproate  ↑ lamotrigine  Increased lamotrigine concentrations slightly more than 2 fold.
 ? valproate  Decreased valproate concentrations an average of 25% over a 3 week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
Table II. Clinically significant drug interactions with theophylline.Refer to PRECAUTIONS, Drug Interactions for further information regarding table.
Drug Type of Interaction EffectAverage effect on steady-state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.
Adenosine Theophylline blocks adenosine receptors. Higher doses of adenosine may be required to achieve desired effect.
Alcohol A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours. 30% increase
Allopurinol Decreases theophylline clearance at allopurinol doses ≥600 mg/day. 25% increase
Aminoglutethimide Increases theophylline clearance by induction of microsomal enzyme activity. 25% decrease
Carbamazepine Similar to aminoglutethimide. 30% decrease
Cimetidine Decreases theophylline clearance by inhibiting cytochrome P450 1A2. 70% increase
Ciprofloxacin Similar to cimetidine. 40% increase
Clarithromycin Similar to erythromycin. 25% increase
Diazepam Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram Decreases theophylline clearance by inhibiting hydroxylation and demethylation. 50% increase
Enoxacin Similar to cimetidine. 300% increase
Ephedrine Synergistic CNS effects Increased frequency of nausea, nervousness, and insomnia.
Erythromycin Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3. 35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown. 30% increase
Flurazepam Similar to diazepam. Similar to diazepam.
Fluvoxamine Similar to cimetidine. Similar to cimetidine.
Halothane Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines. Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-A Decreases theophylline clearance. 100% increase
Isoproterenol (IV) Increase theophylline clearance. 20% increase
Ketamine Pharmacologic May lower theophylline seizure threshold.
Lithium Theophylline increases renal lithium clearance. Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam Similar to diazepam. Similar to diazepam.
Methotrexate (MTX) Decreases theophylline clearance. 20% increase after low dose MTX, higher dose MTX may have a greater effect.
Mexiletine Similar to disulfiram. 80% increase
Midazolam Similar to diazepam. Similar to diazepam.
Moricizine Increases theophylline clearance. 25% decrease
Pancuronium Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition. Larger dose of pancuronium may be required to achieve neuromuscular blockade.
Pentoxifylline Decreases theophylline clearance. 30% increase
Phenobarbital (PB) Similar to aminoglutethimide. 25% decrease after two weeks of concurrent PB.
Phenytoin Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption. Serum theophylline and phenytoin concentrations decrease about 40%.
Propafenone Decreases theophylline clearance and pharmacologic interaction. 40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Propranolol Similar to cimetidine and pharmacologic interaction. 100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Rifampin Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity. 20 to 40% decrease
Sulfinpyrazone Increase theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline. 20% increase
Tacrine Similar to cimetidine, also increases renal clearance of theophylline. 90% increase
Thiabendazole Decreases theophylline clearance. 190% increase
Ticlopidine Decreases theophylline clearance. 60% increase
Troleandomycin Similar to erythromycin. 33 to 100% increase depending on troleandomycin dose.
Verapamil Similar to disulfiram. 20% increase


Table name:
Drugs That Interfere with Hemostasis
Clinical Impact: Indomethacin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of indomethacin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of indomethacin with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ see Warnings and Precautions ( 5.11 )].
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ see Warnings and Precautions ( 5.2 ) ].
Intervention: Concomitant use of indomethacin capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions ( 5.11 )].Indomethacin is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: During concomitant use of indomethacin capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.During concomitant use of indomethacin capsules and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ see Warnings and Precautions ( 5.6 )].When these drugs are administered concomitantly, patients should be adequately hydrated.  Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.It has been reported that the addition of triamterene to a maintenance schedule of Indomethacin resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin and triamterene should not be administered together.Both indomethacin and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently [ see Warnings and Precautions ( 5.6 )].
Intervention: Indomethacin and triamterene should not be administered together. During concomitant use of indomethacin capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects. Be aware that indomethacin and potassium-sparing diuretics may both be associated with increased serum potassium levels. [ see Warnings and Precautions ( 5.6 )].
Digoxin
Clinical Impact: The concomitant use of indomethacin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of indomethacin capsules and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of indomethacin capsules and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of indomethacin capsules and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of indomethacin capsules and cyclosporine may increase cyclosporine's nephrotoxicity.
Intervention: During concomitant use of indomethacin capsules and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ see Warnings and Precautions ( 5.2 )]. Combined use with diflunisal may be particularly hazardous because diflunisal causes significantly higher plasma levels of indomethacin [see Clinical Pharmacology ( 12.3 )].In some patients, combined use of indomethacin and diflunisal has been associated with fatal gastrointestinal hemorrhage.
Intervention: The concomitant use of indomethacin with other NSAIDs or salicylates, especially diflunisal, is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of indomethacin capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of indomethacin capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Probenecid
Clinical Impact: When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased.
Intervention: During the concomitant use of indomethacin and probenecid, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect.  When increases in the dose of indomethacin are made, they should be made carefully and in small increments.


Table name:
Table 7 Summary of AED Interactions with Oxcarbazepine Tablets, USP
AED Coadministered Dose of AED
(mg/day)
Oxcarbazepine Tablets Dose
(mg/day)
Influence of Oxcarbazepine Tablets on AED Concentration
(Mean Change, 90% Confidence Interval)
Influence of AED on MHD Concentration
(Mean Change, 90% Confidence Interval)
Carbamazepine 400-2000 900 nc nc denotes a mean change of less than 10% 40% decrease
[CI: 17% decrease, 57% decrease]
Phenobarbital 100-150 600-1800 14% increase
[CI: 2% increase, 24% increase]
25% decrease
[CI: 12% decrease, 51% decrease]
Phenytoin 250-500 600-1800
>1200-2400
nc , Pediatrics up to 40% increase Mean increase in adults at high oxcarbazepine tablets, USP doses
[CI: 12% increase, 60% increase]
30% decrease
[CI: 3% decrease, 48% decrease]
Valproic acid 400-2800 600-1800 nc 18% decrease
[CI: 13% decrease, 40% decrease]


Table name:
 Digoxin concentrations increased greater than 50%
        Digoxin Serum     
Concentration
Increase
      Digoxin AUC     
Increase
 Recommendations
 Quinidine  NA   54-83% Measure serum digoxin concentrations before     
initiating concomitant drugs. Reduce digoxin
concentrations by decreasing dose by
approximately 30-50% or by modifying the
dosing frequency and continue monitoring.
 Ritonavir  NA  86%
 Digoxin concentrations increased less than 50%
 Amiodarone  17%  40% Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring.
 Propafenone  28%  29%
 Quinine  NA  34-38%
 Spironolactone       NA  44%
 Verapamil  NA  24%


Table name:
Drug Description of Interaction
Tolbutamide;
Sulfonylureas
Hypoglycemia potentiated
Methotrexate Decreases tubular reabsorption; clinical toxicity from methotrexate can result
Oral Anticoagulants Increased bleeding


Table name:
Table 2. Drugs That May Decrease T4 Absorption (Hypothyroidism)
Potential impact: Concurrent use may reduce the efficacy of SYNTHROID by binding and delaying or preventing absorption, potentially resulting in hypothyroidism.
Drug or Drug Class Effect
Calcium Carbonate
Ferrous Sulfate
Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer SYNTHROID at least 4 hours apart from these agents.
Orlistat Monitor patients treated concomitantly with orlistat and SYNTHROID for changes in thyroid function.
Bile Acid Sequestrants
- Colesevelam
- Cholestyramine
- Colestipol
Ion Exchange Resins
- Kayexalate
- Sevelamer
Bile acid sequestrants and ion exchange resins are known to decrease levothyroxine absorption. Administer SYNTHROID at least 4 hours prior to these drugs or monitor TSH levels.
Other drugs:
Proton Pump Inhibitors
Sucralfate
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Gastric acidity is an essential requirement for adequate absorption of levothyroxine. Sucralfate, antacids and proton pump inhibitors may cause hypochlorhydria, affect intragastric pH, and reduce levothyroxine absorption. Monitor patients appropriately.


Table name:
Digoxin concentrations increased greater than 50%
NA – Not available/reported
Digoxin Serum Concentration Increase Digoxin AUC Increase Recommendations
Amiodarone 70% NA Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30 to 50% or by modifying the dosing frequency and continue monitoring.
Captopril 58% 39%
Clarithromycin NA 70%
Dronedarone NA 150%
Gentamicin 129 to 212% NA
Erythromycin 100% NA
Itraconazole 80% NA
Lapatinib NA 180%
Nitrendipine 57% 15%
Propafenone NA 60 to 270%
Quinidine 100% NA
Ranolazine 50% NA
Ritonavir NA 86%
Telaprevir 50% 85%
Tetracycline 100% NA
Verapamil 50 to 75% NA
Digoxin concentrations increased less than 50%
Atorvastatin 22% 15% Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15 to 30% or by modifying the dosing frequency and continue monitoring.
Carvedilol 16% 14%
Conivaptan 33% 43%
Diltiazem 20% NA
Indomethacin 40% NA
Nefazodone 27% 15%
Nifedipine 45% NA
Propantheline 24% 24%
Quinine NA 33%
Raberprazole 29% 19%
Saquinavir 27% 49%
Spironolactone 25% NA
Telmisartan 20 to 49% NA
Teicagrelor 31% 28%
Tolvaptan 30% NA
Trimethoprim 22 to 28% NA
Digoxin concentrations increased, but magnitude is unclear
Alprazolam, azithromycin, cyclosporine, diclofenac, diphenoxylate, epoprostenol, esomeprazole, ibuprofen, ketoconazole, lansoprazole, metformin, omeprazole Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin concentrations decreased
Acarbose, activated charcoal, albuterol, antacids, certain cancer chemotherapy or radiation therapy, cholestyramine, colestipol, extenatide, kaolin-pectin, meals high in bran, metoclopramide, miglitol, neomycin, penicillamine, phenytoin, rifampin, St. John's Wort, sucralfate, sulfasalazine Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20 to 40% as necessary.


Table name: Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology (12.3)]. Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see Clinical Pharmacology (12.3)]. There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole.
Antiretrovirals
Clinical Impact: The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known.
Intervention: Rilpivirine-containing products: Concomitant use with omeprazole is contraindicated [see Contraindications (4)]. Atazanavir: Avoid concomitant use with omeprazole. See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with omeprazole. See prescribing information for nelfinavir. Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities. Other antiretrovirals: See prescribing information for specific antiretroviral drugs.
Warfarin
Clinical Impact: Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
Intervention: Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range.
Methotrexate
Clinical Impact: Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions (5.11)].
Intervention: A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate.
CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam)
Clopidogrel
Clinical Impact: Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology (12.3)]. There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel.
Intervention: Avoid concomitant use with omeprazole. Consider use of alternative
anti-platelet therapy [see Warnings and Precautions (5.6)].
Citalopram
Clinical Impact: Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology (12.3)].
Intervention: Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.
Cilostazol
Clinical Impact: Increased exposure of one of the active metabolites of cilostazol
(3,4-dihydro-cilostazol) [see Clinical Pharmacology (12.3)].
Intervention: Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.
Phenytoin
Clinical Impact: Potential for increased exposure of phenytoin.
Intervention: Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin.
Diazepam
Clinical Impact: Increased exposure of diazepam [see Clinical Pharmacology (12.3)].
Intervention: Monitor patients for increased sedation and reduce the dose of diazepam as needed.
Digoxin
Clinical Impact: Potential for increased exposure of digoxin [see Clinical Pharmacology (12.3)].
Intervention: Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)
Clinical Impact: Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
Intervention: Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF [see Clinical Pharmacology (12.3)]. See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact: Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions.
Intervention: See Contraindications, Warnings and Precautions in prescribing information for clarithromycin. See Drug Interactions in prescribing information for amoxicillin.
Tacrolimus
Clinical Impact: Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.
Intervention: Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact: Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions (5.10), Clinical Pharmacology (12.2)].
Intervention: Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
Interaction with Secretin Stimulation Test
Clinical Impact: Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention: Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology (12.2)].
False Positive Urine Tests for THC
Clinical Impact: There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.
Intervention: An alternative confirmatory method should be considered to verify positive results.
Other
Clinical Impact: There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram).
Intervention: Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole.


Table name:
Interacting Drug
Interaction
Multivalent cation-containing products including antacids,
metal cations or didanosine
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. ( 2.4, 7.1)
Warfarin
Effect may be enhanced. Monitor prothrombin
time, INR, watch for bleeding ( 7.2)
Antidiabetic agents
Carefully monitor blood glucose ( 5.12, 7.3)


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may
result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-
   containing radiographic
   contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which
may result in hyperthyroidism
Amiodarone
Iodide (including iodine-
containing Radiographic
contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase Drugs that may decrease
serum TBG concentration serum TBG concentration
Clofibrate Androgens / Anabolic Steroids
Estrogen-containing oral Asparaginase
   contraceptives Glucocorticoids
Estrogens (oral) Slow-Release Nicotinic Acid
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal
Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake
Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
NITROPRUSSIDE
Para-aminosalicylate sodium
Perphenazine
Resorcinol
 (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Antiretrovirals
        Clinical Impact: The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology (12.3)]. Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see Clinical Pharmacology (12.3)]. There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole.
        Intervention: Rilpivirine-containing products: Concomitant use with omeprazole is contraindicated [see Contraindications (4)].

Atazanavir: Avoid concomitant use with omeprazole. See prescribing information for atazanavir for dosing information.

Nelfinavir: Avoid concomitant use with omeprazole. See prescribing information for nelfinavir.

Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities.

Other antiretrovirals: See prescribing information for specific antiretroviral drugs.
Warfarin
Clinical Impact: Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
Intervention: Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range.
Methotrexate
Clinical Impact: Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions (5.11)].
Intervention: A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate.
CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam)
Clopidogrel
Clinical Impact: Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology (12.3)].

There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel.
Intervention: Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy [see Warnings and Precautions (5.6)].
Citalopram
Clinical Impact: Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology (12.3)].
Intervention: Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.
Cilostazol
Clinical Impact: Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology (12.3)].
Intervention: Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.
Phenytoin
Clinical Impact: Potential for increased exposure of phenytoin.
Intervention: Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin.
Diazepam
Clinical Impact: Increased exposure of diazepam [see Clinical Pharmacology (12.3)].
Intervention: Monitor patients for increased sedation and reduce the dose of diazepam as needed.
Digoxin
Clinical Impact: Potential for increased exposure of digoxin [see Clinical Pharmacology (12.3)].
Intervention: Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)
Clinical Impact: Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
     Intervention: Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF [see Clinical Pharmacology (12.3)].

See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact: Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated.
Amoxicillin also has drug interactions.
Intervention: See Contraindications, Warnings and Precautions in prescribing information for clarithromycin.

See Drug Interactions in prescribing information for amoxicillin.
Tacrolimus
Clinical Impact: Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.
Intervention: Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact: Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions (5.10), Clinical Pharmacology (12.2)].
  Intervention: Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
Interaction with Secretin Stimulation Test
Clinical Impact: Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention: Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology (12.2)].
False Positive Urine Tests for THC
Clinical Impact: There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.
Intervention: An alternative confirmatory method should be considered to verify positive results.
Other
Clinical Impact: There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram).
Intervention: Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole.


Table name:
Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin,
heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole,
prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen,
ibuprofen, indomethacin, ketoprofen,
ketorolac, mefenamic acid, naproxen,
oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone.


Table name:
Interacting Drug 
Interaction
Multivalent cation-containing
products including antacids,
metal cations or didanosine
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidibetic agents
Carefully monitor blood glucose (5.11, 7.3)


Table name:
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Do not exceed 40 mg atorvastatin daily


Table name:
Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
* Change relative to reference
Coadministered Drug
Dosing Schedule
Effect on Active
Moiety (Risperidone + 9-
Hydroxy- Risperidone (Ratio*)
Risperidone Dose
Recommendation

Coadministered Drug
Risperidone
AUC
Cmax

Enzyme (CYP2D6)
Inhibitors





Fluoxetine
20 mg/day 
2 or 3 mg twice
daily
1.4 
1.5
Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine
10 mg/day 
4 mg/day
1.3
-
Re-evaluate dosing. 

20 mg/day 
4 mg/day
1.6
-
Do not exceed 8 mg/day

40 mg/day 
4 mg/day
1.8
-

Enzyme (CYP3A/ PgP inducers) Inducers





Carbamazepine 
573 ± 168 mg/day
3 mg twice daily
0.51 
0.55
Titrate dose upwards.
Do not exceed twice the patient’s usual dose
Enzyme (CYP3A)
Inhibitors





Ranitidine 
150 mg twice daily
1 mg single dose
1.2 
1.4
Dose adjustment not
needed
Cimetidine 
400 mg twice daily
1 mg single dose
1.1 
1.3
Dose adjustment not
needed
Erythromycin 

500 mg four times
daily
1 mg single dose
1.1 
0.94
Dose adjustment not
needed






Other Drugs





Amitriptyline 
50 mg twice daily
3 mg twice daily
1.2 
1.1
Dose adjustment not
needed


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
 Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration  Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
 Drugs that may alter T 4 and T 3 metabolism
 Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T 4 and T 3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT 4. Continued administration results in a decrease in serum T 4 and normal FT 4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T 4 and T 3 to TBG and transthyretin. An initial increase in serum FT 4, is followed by return of FT 4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T 4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T 4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T 4 to T 3, leading to decreased T 3 levels. However, serum T 4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T 3 and T 4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T 3 concentrations by 30% with minimal change in serum T 4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T 3 and T 4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
AED  Coadministered
AED  Concentration
Topiramate 
Concentration

a = Plasma concentration increased 25% in some patients, generally those on a twice
a day dosing regimen of phenytoin.
b = Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated
Phenytoin
NC or 25% increasea
48% decrease
Carbamazepine (CBZ)
NC
40% decrease
CBZ epoxideb
NC
NE
Valproic acid
11% decrease
14% decrease
Phenobarbital
NC 
NE
Primidone
NC
NE
Lamotrigine
NC at TPM doses up to 400 mg/day
13% decrease



Table name:
Antibiotics Anticonvulsants Other Drugs/Dietary Supplements
nafcillin rifampin carbamazepine oxcarbazepine phenobarbital phenytoin bosentan octreotide orlistat sulfinpyrazone terbinafine ticlopidine St. John’s Wort


Table name:
Table II. Clinically significant drug interactions with theophylline*.
Drug Type of Interaction Effect†
 *    Refer to PRECAUTIONS, Drug Interactions for further information regarding table.
†    Average effect on steady state theophylline concentration or other clinical effect for pharmacologic
      interactions. Individual patients may experience larger changes in serum theophylline concentration
      than the value listed.
 Adenosine  Theophylline blocks adenosine
receptors.
 Higher doses of adenosine may be required to achieve
desired effect.
 Alcohol  A single large dose of alcohol (3
mL/kg of whiskey) decreases
theophylline clearance for up to
24 hours.
 30% increase
 Allopurinol  Decreases theophylline clearance
at allopurinol doses ≥600 mg/day.
 25% increase
 Aminoglutethimide  Increases theophylline clearance
by induction of microsomal
enzyme activity.
 25% decrease
 Carbamazepine  Similar to aminoglutethimide.  30% decrease
 Cimetidine  Decreases theophylline clearance
by inhibiting cytochrome P450
1A2.
 70% increase
 Ciprofloxacin  Similar to cimetidine.  40% increase
 Clarithromycin  Similar to erythromycin.  25% increase
 Diazepam  Benzodiazepines increase CNS
concentrations of adenosine, a
potent CNS depressant, while
theophylline blocks adenosine
receptors.
 Larger diazepam doses may be required to produce
desired level of sedation. Discontinuation of
theophylline without reduction of diazepam dose may
result in respiratory depression.
 Disulfiram  Decreases theophylline clearance
by inhibiting hydroxylation and
demethylation.
 50% increase
 Enoxacin  Similar to cimetidine.  300% increase
 Ephedrine  Synergistic CNS effects.  Increased frequency of nausea, nervousness, and
insomnia.
 Erythromycin  Erythromycin metabolite
decreases theophylline clearance
by inhibiting cytochrome P450
3A3.
 35% increase. Erythromycin steady-state serum
concentrations decrease by a similar amount.
 Estrogen  Estrogen containing oral
contraceptives decrease
theophylline clearance in a dose-
dependent fashion. The effect of
progesterone on theophylline
clearance is unknown.
 30% increase
 Flurazepam  Similar to diazepam.  Similar to diazepam.
 Fluvoxamine  Similar to cimetidine.  Similar to cimetidine
 Halothane  Halothane sensitizes the
myocardium to catecholamines,
theophylline increases release of
endogenous catecholamines.
 Increased risk of ventricular arrhythmias.
 Interferon, human
recombinant alpha-A
 Decreases theophylline clearance.  100% increase
 Isoproterenol (IV)  Increases theophylline clearance.  20% decrease
 Ketamine  Pharmacologic.  May lower theophylline seizure threshold.
 Lithium  Theophylline increases renal
lithium clearance.
 Lithium dose required to achieve a therapeutic serum
concentration increased an average of 60%.
 Lorazepam  Similar to diazepam.  Similar to diazepam.
 Methotrexate (MTX)  Decreases theophylline clearance.  20% increase after low dose MTX, higher dose MTX
may have a greater effect.
 Mexiletine  Similar to disulfiram.  80% increase
 Midazolam  Similar to diazepam.  Similar to diazepam.
 Moricizine  Increases theophylline clearance.  25% decrease
 Pancuronium  Theophylline may antagonize
non-depolarizing neuromuscular
blocking effects, possibly due to
phosphodiesterase inhibition.
 Larger dose of pancuronium may be required to
achieve neuromuscular blockade
 Pentoxifylline  Decreases theophylline clearance.  30% increase
 Phenobarbital (PB)  Similar to aminoglutethimide.  25% decrease after two weeks of concurrent PB.
 Phenytoin  Phenytoin increases theophylline
clearance by increasing
microsomal enzyme activity.
Theophylline decreases
phenytoin absorption.
 Serum theophylline and phenytoin concentrations
decrease about 40%.
 Propafenone  Decreases theophylline clearance
and pharmacologic interaction.
 40% increase. Beta2 blocking effect may decrease
efficacy of theophylline
 Propranolol  Similar to cimetidine and
pharmacologic interaction.
 100% increase. Beta2 blocking effect may decrease
efficacy of theophylline
 Rifampin  Increases theophylline clearance
by increasing cytochrome P450
1A2 and 3A3 activity.
 20-40% decrease
 St. John's Wort
(Hypericum
Perforatum)
 Decrease in theophylline plasma
concentrations.
 Higher doses of theophylline may be required to
achieve desired effect. Stopping St. John's Wort may
result in theophylline toxicity.
 Sulfinpyrazone  Increases theophylline clearance
by increasing demethylation and
hydroxylation. Decreases renal
clearance of theophylline.
 20% decrease
 Tacrine  Similar to cimetidine, also
increases renal clearance of
theophylline.
 90% increase
 Thiabendazole  Decreases theophylline clearance.  190% increase
 Ticlopidine  Decreases theophylline clearance.  60% increase
 Troleandomycin  Similar to erythromycin.  33-100% increase depending on troleandomycin dose.
 Verapamil  Similar to disulfiram.  20% increase


Table name:
 Factors  Dosage Adjustments for Aripiprazole
 Known CYP2D6 Poor Metabolizers  Administer half of usual dose
 Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors  Administer a quarter of usual dose
 Strong CYP2D6 or CYP3A4 inhibitors  Administer half of usual dose
 Strong CYP2D6 and CYP3A4 inhibitors  Administer a quarter of usual dose
 Strong CYP3A4 inducers  Double usual dose over 1 to 2 weeks


Table name:
Bleeding times
Clinical Impact: Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention: This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact: The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention: Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact: Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention: This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.


Table name:
Interacting Drug
Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.12, 7.3)


Table name:
Effects on Steady-State Fexofenadine Pharmacokinetics After 7 Days of Co-Administration with Fexofenadine Hydrochloride 120 mg Every 12 Hours (two times the recommended twice daily dose) in Healthy Volunteers (n=24)
Concomitant Drug Cmax SS
(Peak plasma concentration)
AUCSS(0–12h)
(Extent of systemic exposure)
Erythromycin
(500 mg every 8 hrs)
+82% +109%
Ketoconazole
(400 mg once daily)
+135% +164%


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant  Drug
Effect  on  Concentration  of  Lamotrigine  or 
Concomitant  Drug
Clinical  Comment 
↓= Decreased (induces lamotrigine gluronidation).
↑= Increased (inhibits lamotrigine glucuronidation).
?= Conflicting data.
Estrogen-containing oral  contraceptive preparations  containing 30 mcg ethinylestradiol  and 150 mcg levonorgestrel



↓ lamotrigine




Decreased lamotrigine levels  approximately 50%.





↓ levonorgestrel
Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and  CBZ epoxide

↓ lamotrigine

Addition of carbamazepine decreases lamotrigine  concentration approximately 40%.



? CBZ epoxide
May increase CBZ epoxide levels
Phenobarbital/Primidone
↓ lamotrigine
Decreased lamotrigine  concentration approximately 40%.

Phenytoin (PHT)
↓ lamotrigine
Decreased lamotrigine  concentration approximately 40%

Rifampin
↓ lamotrigine
Decreased lamotrigine AUC  approximately 40%

Valproate
↑ lamotrigine

Increased lamotrigine concentrations slightly  more than 2-fold.



? valproate
Decreased valproate concentrations an average of  25% over a 3-week period then stabilized in healthy volunteers;  no change in controlled clinical trials in epilepsy patients.





Table name: Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.During concomitant use of diclofenac sodium delayed-release tablets and ACE-inhibitors, ARBs, or beta- blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of diclofenac sodium delayed-release tablets and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS: Renal Toxicity and Hyperkalemia ). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Table 2. Clinically Significant Drug Interactions with Diclofenac
Drugs That Interfere with Hemostasis
Clinical Impact:
Intervention: Monitor patients with concomitant use of diclofenac sodium delayed-release tablets with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS: Hematologic Toxicity ).
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation ).
Intervention: Concomitant use of diclofenac sodium delayed-release tablets and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS: Hematologic Toxicity ). Diclofenac sodium delayed-release tablets are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:
Intervention:
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of diclofenac sodium delayed-release tablets with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS: Renal Toxicity and Hyperkalemia ).
Digoxin
Clinical Impact: The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of diclofenac sodium delayed-release tablets and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of diclofenac sodium delayed-release tablets and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of diclofenac sodium delayed-release tablets and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of diclofenac sodium delayed-release tablets and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of diclofenac sodium delayed-release tablets and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation ).
Intervention: The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of diclofenac sodium delayed-release tablets and pemetrexed may increase the risk of pemetrexed‑ associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of diclofenac sodium delayed-release tablets and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
CYP2C9 Inhibitors or Inducers:
Clinical Impact: Diclofenac is metabolized by cytochrome P450 enzymes, predominantly by CYP2C9. Co-administration of diclofenac with CYP2C9 inhibitors (e.g. voriconazole) may enhance the exposure and toxicity of diclofenac whereas co‑administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of diclofenac.
Intervention: A dosage adjustment may be warranted when diclofenac is administered with CYP2C9 inhibitors or inducers (see CLINICAL PHARMACOLOGY: Pharmacokinetics ).


Table name:
Drug Interactions Associated with Increased Risk of  Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice Avoid grapefruit juice


Table name:
Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s) Recommendation Comments
Tizanidine Contraindicated Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)].
Theophylline Avoid Use (Plasma Exposure Likely to be Increased and Prolonged) Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions (5.6).]
Drugs Known to Prolong QT Interval Avoid Use Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.10) and Use in Specific Populations (8.5)].
Oral antidiabetic drugs Use with caution Glucose-lowering effect potentiated Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported . Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs. [see Adverse Reactions (6.1).]
Phenytoin Use with caution Altered serum levels of phenytoin (increased and decreased) To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after coadministration of ciprofloxacin with phenytoin.
Cyclosporine Use with caution (transient elevations in serum creatinine) Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs Use with caution (Increase in anticoagulant effect) The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole Use with caution Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after coadministration with ciprofloxacin [see Warnings and Precautions (5.15)].
Clozapine Use with caution Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs Use with caution Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil Use with caution 2-fold increase in exposure Monitor for sildenafil toxicity (see Pharmacokinetics -(12.3)-] .
Duloxetine Avoid Use 5-fold increase in duloxetine exposure If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx ® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products) Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2)]. Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels) Potentiation of ciprofloxacin toxicity may occur.


Table name: Use of sildenafil (Revatio) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) [see Contraindications (4.2)].

The following dose adjustments are recommended for use of tadalafil (Adcirca) with APTIVUS/ritonavir:
Co-administration of tadalafil (Adcirca) in patients on APTIVUS/ritonavir:

In patients receiving APTIVUS/ritonavir for at least one week, start Adcirca at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Co-administration of APTIVUS/ritonavir in patients on tadalafil (Adcirca):

Avoid use of tadalafil (Adcirca) during the initiation of APTIVUS/ritonavir. Stop Adcirca at least 24 hours prior to starting APTIVUS/ritonavir. After at least one week following the initiation of APTIVUS/ritonavir, resume Adcirca at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.
↑ increase, ↓ decrease, ↔ no change, ↕ unable to predict
Concomitant Drug Class:
Drug name
Effect on Concentration of Tipranavir or Concomitant Drug Clinical Comment

HIV-1 Antiviral Agents
Fusion Inhibitors:    

Enfuvirtide

↑ Tipranavir
At steady state, tipranavir trough concentrations were approximately 45% higher in patients co-administered enfuvirtide in the Phase 3 trials. The mechanism for this increase is not known. Dose adjustments are not recommended.
Non-Nucleoside Reverse Transcriptase
Inhibitors:    

Etravirine

↓ Etravirine

APTIVUS/ritonavir when coadministered with etravirine may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of etravirine. Etravirine and APTIVUS/ritonavir should not be coadministered.
 
Rilpivirine The use of rilpivirine co-administered with APTIVUS/ritonavir has not been studied. Concomitant use of rilpivirine with Aptivus/ritonavir may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). Rilpivirine is not expected to affect the plasma concentrations of Aptivus/ritonavir.
 
Nucleoside Reverse Transcriptase    
Inhibitors:  

Abacavir

↓ Abacavir AUC by approximately 40%

Clinical relevance of reduction in abacavir levels not established. Dose adjustment of abacavir cannot be recommended at this time.
 
Didanosine (EC) ↓ Didanosine Clinical relevance of reduction in didanosine levels not established. For optimal absorption, didanosine should be separated from APTIVUS/ritonavir dosing by at least 2 hours.
 
Zidovudine ↓ Zidovudine AUC by approximately 35%. ZDV glucuronide concentrations were unaltered. Clinical relevance of reduction in zidovudine levels not established. Dose adjustment of zidovudine cannot be recommended at this time.
Protease Inhibitors (co-administered with 200 mg of ritonavir):
 
 
Fosamprenavir
Lopinavir
Saquinavir
↓ Amprenavir
↓ Lopinavir
↓ Saquinavir
Combining a protease inhibitor with APTIVUS/ritonavir is not recommended.

Protease Inhibitors (co-administered with 100 mg of ritonavir):
 
 
Atazanavir ↓ Atazanavir
↑ Tipranavir
 
Virus Integrase Strand Transfer Inhibitors:
 
   
Raltegravir ↓ Raltegravir APTIVUS/ritonavir reduces plasma concentrations of raltegravir. Since comparable efficacy was observed for this combination in phase 3 studies, dose adjustment is not recommended.

Agents for Opportunistic Infections
 
Antifungals:
 
 
Fluconazole
Itraconazole
Ketoconazole
Voriconazole
↑ Tipranavir, ↔ Fluconazole Fluconazole increases tipranavir concentrations but dose adjustments are not needed. Fluconazole doses >200 mg/day are not recommended.
↑ Itraconazole (not studied)  
↑ Ketoconazole (not studied) Based on theoretical considerations itraconazole and ketoconazole should be used with caution. High doses (>200 mg/day) are not recommended.
↕ Voriconazole (not studied)  
  Due to multiple enzymes involved with voriconazole metabolism, it is difficult to predict the interaction.
Antimycobacterials:
 
 
Clarithromycin ↑ Tipranavir, ↑ Clarithromycin,
↓ 14-hydroxy-clarithromycin metabolite
No dose adjustment of APTIVUS or clarithromycin for patients with normal renal function is necessary.
 
  For patients with renal impairment the following dosage adjustments should be considered: For patients with CLCR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients with CLCR <30 mL/min the dose of clarithromycin should be decreased by 75%.
Rifabutin Tipranavir not changed,
↑ Rifabutin
↑ Desacetyl-rifabutin
Single dose study. Dosage reductions of rifabutin by 75% are recommended (e.g., 150 mg every other day). Increased monitoring for adverse events in patients receiving the combination is warranted. Further dosage reduction may be necessary.
 
Other Agents Commonly Used
 
Anticonvulsants:
 
Carbamazepine
Phenobarbital
Phenytoin
↓ Tipranavir Caution should be used when prescribing carbamazepine, phenobarbital and/or phenytoin. APTIVUS may be less effective due to decreased tipranavir plasma concentration in patients taking these agents concomitantly.
 
Valproic Acid ↓ Valproic Acid Caution should be used when prescribing valproic acid. Valproic acid may be less effective due to decreased valproic acid plasma concentration in patients taking APTIVUS concomitantly.
Antidepressants:    
 
Trazodone ↑ Trazodone Concomitant use of trazodone and APTIVUS/ritonavir may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP 3A4 inhibitor such as APTIVUS/ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered.
 
Desipramine Combination with APTIVUS/ritonavir not studied
↑ Desipramine
Dosage reduction and concentration monitoring of desipramine is recommended.
 
Selective Serotonin-Reuptake Inhibitors: Combination with APTIVUS/ritonavir not studied Antidepressants have a wide therapeutic index, but doses may need to be adjusted upon initiation of APTIVUS/ritonavir therapy.
Fluoxetine
Paroxetine
Sertraline
↑ Fluoxetine
↑ Paroxetine
↑ Sertraline
 
Anti-HCV agents:
 
Boceprevir Co-administration of APTIVUS and boceprevir has not been studied. With concomitant use, changes in exposure were observed both for boceprevir and certain protease inhibitors used for the treatment of HIV-1 infection or either medication. Information is not available regarding tipranavir or boceprevir exposure with concomitant use. It is not recommended to co-administer boceprevir with APTIVUS/ritonavir.

Telaprevir Co-administration of APTIVUS and telaprevir has not been studied. With concomitant use, changes in exposure were observed both for telaprevir and certain protease inhibitors used for the treatment of HIV-1 infection or telaprevir. Information is not available regarding tipranavir or telaprevir exposure with concomitant use. It is not recommended to co-administer telaprevir with APTIVUS/ritonavir.
 
Anti-gout:
 
Colchicine ↑ Colchicine In patients with renal or hepatic impairment, coadministration of colchicine in patients on APTIVUS/ritonavir is contraindicated.

In combination with APTIVUS/ritonavir, the following dosage adjustments are recommended in patients with normal renal and hepatic function:

Treatment of gout flares: Co-administration of colchicine in patients on APTIVUS/ritonavir: 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares: Co-administration of colchicine in patients on APTIVUS/ritonavir : If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF): Co-administration of colchicine in patients on APTIVUS/ritonavir: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Antipsychotics:
 
Quetiapine ↑ Quetiapine Initiation of APTIVUS with ritonavir in patients taking quetiapine:

Consider alternative antiretroviral therapy to avoid increases in quetiapine exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring.

Initiation of quetiapine in patients taking APTIVUS with ritonavir:

Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.
 
Benzodiazepines:  
 
Parenterally administered midazolam ↑ Midazolam Midazolam is extensively metabolized by CYP 3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, APTIVUS should not be given with orally administered midazolam [ see Contraindications (4) ]. If APTIVUS is co-administered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustments should be considered.
Buprenorphine/naloxone ↔ Buprenorphine
↓ Tipranavir
APTIVUS/ritonavir did not result in changes in the clinical efficacy of buprenorphine/naloxone. Compared to historical controls tipranavir Cmin was decreased approximately 40% with this combination. Dose adjustments cannot be recommended.
Calcium Channel Blockers:

Diltiazem
Felodipine
Nicardipine
Nisoldipine
Verapamil
Combination with APTIVUS/ritonavir not studied. Cannot predict effect of TPV/ritonavir on calcium channel blockers that are dual substrates of CYP3A and P-gp due to conflicting effect of TPV/ritonavir on CYP3A and P-gp.

↕ Diltiazem
↑ Felodipine (CYP3A substrate but not P-gp substrate)
↕ Nicardipine
↕ Nisoldipine (CYP3A substrate but not clear whether it is a P-gp substrate)
↕ Verapamil
Caution is warranted and clinical monitoring of patients is recommended.
Disulfiram/Metronidazole Combination with TPV/ritonavir not studied APTIVUS capsules contain alcohol that can produce disulfiram-like reactions when co-administered with disulfiram or other drugs which produce this reaction (e.g., metronidazole).
Endothelin receptor antagonists

Bosentan


↑ Bosentan
Co-administration of bosentan in patients on APTIVUS/ritonavir:
In patients who have been receiving APTIVUS/ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

Co-administration of APTIVUS/ritonavir in patients on bosentan:

Discontinue use of bosentan at least 36 hours prior to initiation of APTIVUS/ritonavir.

After at least 10 days following the initiation of APTIVUS/ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
 
HMG-CoA Reductase Inhibitors:
 
 
Atorvastatin
Rosuvastatin
↑ Atorvastatin
↓ Hydroxy-atorvastatin metabolites
↑ Rosuvastatin
Avoid co-administration with atorvastatin.
Hypoglycemics:
 
 
  Combination with APTIVUS/ritonavir not studied Careful glucose monitoring is warranted.
 
Glimepiride
Glipizide
Glyburide
Pioglitazone
↔ Glimepiride (CYP 2C9)
↔ Glipizide (CYP 2C9)
↔ Glyburide (CYP 2C9)
↕ Pioglitazone (CYP 2C8 and CYP 3A4)
 
Repaglinide ↕ Repaglinide (CYP 2C8 and CYP 3A4)  
Tolbutamide ↔ Tolbutamide (CYP 2C9)

The effect of TPV/ritonavir on CYP 2C8 substrate is not known.
 
Immunosuppressants:    
  Combination with APTIVUS/ritonavir not studied. Cannot predict effect of TPV/ritonavir on immunosuppressants due to conflicting effect of TPV/ritonavir on CYP 3A and P-gp. Increased frequency of monitoring of plasma levels of immunosuppressant drugs is recommended.
Cyclosporine
Sirolimus
Tacrolimus
↕ Cyclosporine
↕ Sirolimus
↕ Tacrolimus
 
Inhaled beta agonist:

Salmeterol


↑ Salmeterol
Concurrent administration of APTIVUS/ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.
Inhaled/Nasal Steroids:
 
 
Fluticasone ↑ Fluticasone Concomitant use of fluticasone propionate and APTIVUS/ritonavir may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Co-administration of fluticasone propionate and APTIVUS/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.
Narcotic Analgesics:
 
 
  Combinations with APTIVUS/ritonavir not studied Dosage increase and long-term use of meperidine are not recommended due to increased concentrations of the metabolite normeperidine which has both analgesic activity and CNS stimulant activity (e.g., seizures).
Meperidine ↓ Meperidine, ↑ Normeperidine
 
Methadone ↓ Methadone

↓ S-Methadone, ↓ R-Methadone
Dosage of methadone may need to be increased when co-administered with APTIVUS and 200 mg of ritonavir.
Oral Contraceptives/Estrogens:
 
 
Ethinyl estradiol ↓ Ethinyl estradiol concentrations by 50% Alternative methods of nonhormonal contraception should be used when estrogen based oral contraceptives are co-administered with APTIVUS and 200 mg of ritonavir. Patients using estrogens as hormone replacement therapy should be clinically monitored for signs of estrogen deficiency. Women using estrogens may have an increased risk of non-serious rash.
Proton Pump Inhibitors:    

Omeprazole

↓ Omeprazole, ↔ Tipranavir
Dosage of omeprazole may need to be increased when co-administered with APTIVUS and ritonavir.
 
PDE-5 Inhibitors:  



Sildenafil
Tadalafil
Vardenafil
Only the combination of tadalafil with APTIVUS/ritonavir has been studied (at doses used for treatment of erectile dysfunction).  Co-administration with APTIVUS/ritonavir may result in an increase in PDE-5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism.

↑ Sildenafil (not studied)
↑ Tadalafil with first dose APTIVUS/ritonavir
↔ Tadalafil at APTIVUS/ritonavir steady-state
↑ Vardenafil (not studied)
Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH):
 
  Use of PDE-5 inhibitors for erectile dysfunction:

Concomitant use of PDE-5 inhibitors with APTIVUS/ritonavir should be used with caution and in no case should the starting dose of: sildenafil exceed 25 mg within 48 hours tadalafil exceed 10 mg every 72 hours vardenafil exceed 2.5 mg every 72 hours Use with increased monitoring for adverse events.
Warfarin ↔ S-Warfarin Frequent INR (international normalized ratio) monitoring upon initiation of APTIVUS/ritonavir therapy.


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on
Concentration of Lamotrigine or Concomitant Drug
Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine Decreased lamotrigine concentrations approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? carbamazepine epoxide May increase carbamazepine epoxide levels.
 Lopinavir/ritonavir ↓ lamotrigine Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir ↓ lamotrigine Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine
Increased lamotrigine concentrations slightly more than 2-fold.
? valproate There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.


Table name:
Drugs   That   Interfere   with  Hemostasis
Clinical Impact: ●  Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. ●  Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of celecoxib with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2) ]. In two studies in healthy volunteers, and in patients with osteoarthritis and established heart disease respectively, celecoxib (200-400 mg daily) has demonstrated a lack of interference with the cardioprotective antiplatelet effect of aspirin (100-325 mg).
Intervention: Concomitant use of celecoxib and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11) ]. Celecoxib is not a substitute for low dose aspirin for cardiovascular protection.
ACE   Inhibitors,   Angiotensin   Receptor   Blockers,   and   Beta-Blockers
Clinical Impact: ●  NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). ●  In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: ●  During concomitant use of celecoxib and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. ●  During concomitant use of celecoxib  and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. ●  When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of celecoxib   with  diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Digoxin
Clinical Impact: The concomitant use of celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of celecoxib  and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of celecoxib and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Celecoxib  has no effect on methotrexate pharmacokinetics.
Intervention: During concomitant use of celecoxib and  methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of celecoxib  and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of celecoxib  and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs   and  Salicylates
Clinical Impact: Concomitant use of celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2) ].
Intervention: The concomitant use of celecoxib with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of celecoxib  and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of celecoxib  and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
CYP2C9  Inhibitors  or  inducers
Clinical Impact: Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Co-administration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g., fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g., rifampin) may lead to compromised efficacy of celecoxib.
Intervention: Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers. [see Clinical Pharmacology (12.3) ].
CYP2D6   substrates
Clinical Impact: In vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6 (e.g., atomoxetine), and celecoxib may enhance the exposure and toxicity of these drugs.
Intervention Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2D6 substrates. [see Clinical Pharmacology (12.3)].
Corticosteroids
Clinical Impact: Concomitant use of corticosteroids with celecoxib may increase the risk of GI ulceration or bleeding.
Intervention Monitor patients with concomitant use of celecoxib  with corticosteroids for signs of bleeding [see  Warnings and Precautions (5.2) ].


Table name:
 Factors  Dosage Adjustments for Aripiprazole
 Known CYP2D6 Poor Metabolizers  Administer half of usual dose
 Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors  Administer a quarter of usual dose
 Strong CYP2D6 or CYP3A4 inhibitors  Administer half of usual dose
 Strong CYP2D6 and CYP3A4 inhibitors  Administer a quarter of usual dose
 Strong CYP3A4 inducers  Double usual dose over 1 to 2 weeks


Table name:
Drug Name Effect on Concentration of Nevirapine or Concomitant Drug Clinical Comment
HIV Antiviral Agents: Protease Inhibitors (PIs)
Atazanavir/Ritonavir* ↓ Atazanavir ↑ Nevirapine Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures.
Fosamprenavir* ↓Amprenavir ↑Nevirapine Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.
Fosamprenavir/Ritonavir* ↓Amprenavir ↑Nevirapine No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied.
Indinavir* ↓ Indinavir The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established.
Lopinavir/ Ritonavir* ↓Lopinavir Dosing in adult patients: A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.
Nelfinavir* ↓Nelfinavir M8 Metabolite ↓Nelfinavir Cmin The appropriate doses of the combination of nevirapine and nelfinavir, with respect to safety and efficacy, have not been established.
Saquinavir/ritonavir The interaction between nevirapine and saquinavir/ritonavir has not been evaluated The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz* ↓ Efavirenz The appropriate doses of these combinations with respect to safety and efficacy have not been established.
Delavirdine Etravirine Rilpivirine Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial.
Hepatitis C Antiviral Agents
Boceprevir Plasma concentrations of boceprevir may be decreased due to induction of CYP3A4/5 by nevirapine. Nevirapine and boceprevir should not be coadministered because decreases in boceprevir plasma concentrations may result in a reduction in efficacy.
Telaprevir Plasma concentrations of telaprevir may be decreased due to induction of CYP3A4 by nevirapine and plasma concentrations of nevirapine may be increased due to inhibition of CYP3A4 by telaprevir. Nevirapine and telaprevir should not be coadministered because changes in plasma concentrations of nevirapine, telaprevir, or both may result in a reduction in telaprevir efficacy or an increase in nevirapine-associated adverse events.
Other Agents
Analgesics:
Methadone* ↓ Methadone Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Antiarrhythmics :
Amiodarone, disopyramide, lidocaine Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Antibiotics:
Clarithromycin* ↓ Clarithromycin ↑ 14-OH clarithromycin Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium intracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.
Rifabutin* ↑Rifabutin Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.
Rifampin* ↓ Nevirapine Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Anticonvulsants:
Carbamazepine, clonazepam, ethosuximide Plasma concentrations of nevirapine and the anticonvulsant may be decreased. Use with caution and monitor virologic response and levels of anticonvulsants.
Antifungals:
Fluconazole* ↑Nevirapine Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events.
Ketoconazole* ↓ Ketoconazole Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.
Itraconazole ↓ Itraconazole Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug.
Antithrombotics :
Warfarin Plasma concentrations may be increased. Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.
Calcium channel blockers:
Diltiazem, nifedipine, verapamil Plasma concentrations may be decreased. Appropriate doses for these combinations have not been established.
Cancer chemotherapy:
Cyclophosphamide Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Ergot alkaloids:
Ergotamine Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Immunosuppressants :
Cyclosporine, tacrolimus, sirolimus Plasma concentrations may be decreased. Appropriate doses for these combinations have not been established.
Motility agents:
Cisapride Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Opiate agonists:
Fentanyl Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Oral contraceptives:
Ethinyl estradiol and Norethindrone* ↓ Ethinyl estradiol ↓ Norethindrone Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended.


Table name:
Factors Adjusted Dose
CYP2D6 Poor Metabolizers
CYP2D6 Poor Metabolizers taking concomitant CYP3A4 inhibitors 200 mg200 mg and 160 mg dose adjustments are obtained only by using the 300 mg or 400 mg strength vials.
Patients Taking 400 mg of ABILIFY MAINTENA
Strong CYP2D6 or CYP3A4 inhibitors 300 mg
CYP2D6 and CYP3A4 inhibitors 200 mg
CYP3A4 inducers Avoid use
Patients Taking 300 mg of ABILIFY MAINTENA
Strong CYP2D6 or CYP3A4 inhibitors 200 mg
CYP2D6 and CYP3A4 inhibitors 160 mg
CYP3A4 inducers Avoid use


Table name:
DRUG DESCRIPTION OF INTERACTION
Sulfonylureas Hypoglycemia potentiated.
Methotrexate Decreases tubular reabsorption; clinical toxicity from methotrexate can result.
Oral Anticoagulants Increased bleeding.


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine Decreased lamotrigine levels approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%
Carbamazepine (CBZ) and CBZ epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? CBZ epoxide May increase CBZ epoxide levels
Phenobarbital/Primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT) ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine Increased lamotrigine concentrations slightly more than 2 fold.
? valproate Decreased valproate concentrations an average of 25% over a 3 week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol, famotidine nizatidine
systemic and inhaled felodipine norfloxacin
amoxicillin finasteride ofloxacin
ampicillin, hydrocortisone omeprazole
with or without isoflurane prednisone, prednisolone
sulbactam isoniazid ranitidine
atenolol isradipine rifabutin
azithromycin influenza vaccine roxithromycin
caffeine, ketoconazole sorbitol
  dietary ingestion lomefloxacin (purgative doses do not
cefaclor mebendazole inhibit theophylline
co-trimoxazole medroxyprogesterone absorption)
(trimethoprim and methylprednisolone sucralfate
sulfamethoxazole) metronidazole terbutaline, systemic
diltiazem metoprolol terfenadine
dirithromycin nadolol tetracycline
enflurane nifedipine tocainide


Table name:
Interacting Drug Interaction
Multivalent cation-containing product including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.11, 7.3)


Table name:
Factors   Dosage Adjustment of aripiprazole
 Known CYP2D6 Poor Metabolizers  Administer half of usual dose
 Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors  Administer a quarter of usual dose
 Strong CYP2D6 or CYP3A4 inhibitors  Administer half of usual dose
 Strong CYP2D6 and CYP3A4 inhibitors  Administer a quarter of usual dose
 Strong CYP3A4 inducers  Double usual dose over 1 to 2 weeks


Table name:
Table 2. Clinically Significant Drug Interactions with Diclofenac
Drugs That Interfere with Hemostasis
Clinical Impact: Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of diclofenac sodium delayed-release tablets with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS: Hematologic Toxicity ).
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation ).
Intervention: Concomitant use of diclofenac sodium delayed-release tablets and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS: Hematologic Toxicity ). Diclofenac sodium delayed-release tablets are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: During concomitant use of diclofenac sodium delayed-release tablets and ACE-inhibitors, ARBs, or beta- blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of diclofenac sodium delayed-release tablets and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS: Renal Toxicity and Hyperkalemia ). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of diclofenac sodium delayed-release tablets with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS: Renal Toxicity and Hyperkalemia ).
Digoxin
Clinical Impact: The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of diclofenac sodium delayed-release tablets and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance . The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of diclofenac sodium delayed-release tablets and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of diclofenac sodium delayed-release tablets and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of diclofenac sodium delayed-release tablets and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of diclofenac sodium delayed-release tablets and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation ) .
Intervention: The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of diclofenac sodium delayed-release tablets and pemetrexed may increase the risk of pemetrexed‑ associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of diclofenac sodium delayed-release tablets and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
CYP2C9 Inhibitors or Inducers:
Clinical Impact: Diclofenac is metabolized by cytochrome P450 enzymes, predominantly by CYP2C9. Co-administration of diclofenac with CYP2C9 inhibitors (e.g. voriconazole) may enhance the exposure and toxicity of diclofenac whereas co‑administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of diclofenac.
Intervention: A dosage adjustment may be warranted when diclofenac is administered with CYP2C9 inhibitors or inducers (see CLINICAL PHARMACOLOGY: Pharmacokinetics ).


Table name:
Interacting Agents Prescribing Recommendations
Cyclosporine Do not exceed 10 mg atorvastatin daily
Clarithromycin, itraconazole, HIV protease inhibitors (ritonavir plus saquinavir or lopinavir plus ritonavir) Caution when exceeding doses > 20 mg atorvastatin daily. The lowest dose necessary should be used.


Table name:
Table 2. Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T4 and T3 serum transport - but FT4 concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors
(SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 3 Clinically Significant Drug Interactions with Meloxicam
Drugs  that  Interfere  with  Hemostasis
Clinical  Impact :
Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.
Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention :
Monitor patients with concomitant use of meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ see  Warnings  and  Precautions  ( 5 . 11)].
Aspirin
Clinical  Impact :
Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ see  Warnings  and  Precautions  ( 5 . 2)].
Intervention :
Concomitant use of meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see  Warnings  and  Precautions  ( 5 . 11)].
Meloxicam is not a substitute for low dose aspirin for cardiovascular protection.
ACE  Inhibitors Angiotensin  Receptor  Blockers or  Beta - Blockers
Clinical  Impact :
NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).
In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, coadministration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention :
During concomitant use of meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.
During concomitant use of meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ see  Warnings  and  Precautions  ( 5 . 6 )].
When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical  Impact :
Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam.
Intervention :
During concomitant use of meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ see  Warnings  and  Precautions  ( 5 . 6)].
Lithium
Clinical  Impact :
NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [ see  Clinical  Pharmacology  ( 12 . 3)].
Intervention :
During concomitant use of meloxicam and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical  Impact :
Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention :
During concomitant use of meloxicam and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical  Impact :
Concomitant use of meloxicam and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention :
During concomitant use of meloxicam and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs  and  Salicylates
Clinical  Impact :
Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ see  Warnings  and  Precautions  ( 5 . 2)].
Intervention :
The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical  Impact :
Concomitant use of meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention :
During concomitant use of meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.
Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended.


Table name:
Bleeding times
Clinical Impact: Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention: This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact: The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention: Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact: Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention: This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.


Table name:
Inhibitors of CYP2D6
Clinical Impact:
The concomitant use of tramadol hydrochloride extended-release tablets and CYP2D6 inhibitors may result in an increase in the plasma concentration of tramadol and a decrease in the plasma concentration of M1, particularly when an inhibitor is added after a stable dose of tramadol hydrochloride extended-release tablets is achieved. Since M1 is a more potent µ-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome.

After stopping a CYP2D6 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease and the M1 plasma concentration will increase which could increase or prolong therapeutic effects but also increase adverse reactions related to opioid toxicity, and may cause potentially fatal respiratory depression [see Clinical Pharmacology ( 12.3)] .
Intervention:
If concomitant use of a CYP2D6 inhibitor is necessary, follow patients closely for adverse reactions including opioid withdrawal, seizures, and serotonin syndrome.

If a CYP2D6 inhibitor is discontinued, consider lowering tramadol hydrochloride extended-release tablets dosage until stable drug effects are achieved. Follow patients closely for adverse events including respiratory depression and sedation.
Examples
Quinidine, fluoxetine, paroxetine and bupropion
Inhibitors of CYP3A4
Clinical Impact:
The concomitant use of tramadol hydrochloride extended-release tablets and CYP3A4 inhibitors can increase the plasma concentration of tramadol and may result in a greater amount of metabolism via CYP2D6 and greater levels of M1. Follow patients closely for increased risk of serious adverse events including seizures and serotonin syndrome, and adverse reactions related to opioid toxicity including potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of tramadol hydrochloride extended-release tablets is achieved.

After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease [see Clinical Pharmacology ( 12.3)] , resulting in decreased opioid efficacy and possibly signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol.
Intervention:
If concomitant use is necessary, consider dosage reduction of tramadol hydrochloride extended-release tablets until stable drug effects are achieved. Follow patients closely for seizures and serotonin syndrome, and signs of respiratory depression and sedation at frequent intervals.
If a CYP3A4 inhibitor is discontinued, consider increasing the tramadol hydrochloride extended-release tablets dosage until stable drug effects are achieved and follow patients for signs and symptoms of opioid withdrawal.
Examples
Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)
CYP3A4 Inducers
Clinical Impact:
The concomitant use of tramadol hydrochloride extended-release tablets and CYP3A4 inducers can decrease the plasma concentration of tramadol [see Clinical Pharmacology ( 12.3)] , resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to tramadol, [see Warnings and Precautions ( 5.4)] .
After stopping a CYP3A4 inducer, as the effects of the inducer decline, the tramadol plasma concentration will increase [see Clinical Pharmacology ( 12.3)] , which could increase or prolong both the therapeutic effects and adverse reactions, and may cause seizures and serotonin syndrome, and potentially fatal respiratory depression.
Intervention:
If concomitant use is necessary, consider increasing the tramadol hydrochloride extended-release tablets dosage until stable drug effects are achieved. Follow patients for signs of opioid withdrawal.
If a CYP3A4 inducer is discontinued, consider tramadol hydrochloride extended-release tablets dosage reduction and monitor for seizures and serotonin syndrome, and signs of sedation and respiratory depression.

Patients taking carbamazepine, a CYP3A4 inducer, may have a significantly reduced analgesic effect of tramadol. Because carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of tramadol hydrochloride extended-release tablets and carbamazepine is not recommended.
Examples:
Rifampin, carbamazepine, phenytoin
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact:
Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:
Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions ( 5.5)] .
Examples:
Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact:
The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome .
Intervention:
If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue tramadol hydrochloride extended-release tablets if serotonin syndrome is suspected.
Examples:
Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:
MAOI interactions with opioids may manifest as serotonin syndrome [see Warnings and Precautions ( 5.6)] or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions ( 5.2)].
Intervention:
Do not use tramadol hydrochloride extended-release tablets in patients taking MAOIs or within 14 days of stopping such treatment.
Examples:
phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:
May reduce the analgesic effect of tramadol hydrochloride extended-release tablets and/or precipitate withdrawal symptoms.
Intervention:
Avoid concomitant use.
Examples:
butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact:
Tramadol may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:
Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of tramadol hydrochloride extended-release tablets and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact:
Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:
Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:
The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:
Monitor patients for signs of urinary retention or reduced gastric motility when tramadol hydrochloride extended-release tablets are used concomitantly with anticholinergic drugs.
Digoxin
Clinical Impact:
Post-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity.
Intervention:
Follow patients for signs of digoxin toxicity and adjust the dosage of digoxin as needed.
Warfarin
Clinical Impact:
Post-marketing surveillance of tramadol has revealed rare reports of alteration of warfarin effect, including elevation of prothrombin times.
Intervention:
Monitor the prothrombin time of patients on warfarin for signs of an interaction and adjust the dosage of warfarin as needed.


Table name:
Bleeding times
Clinical Impact: Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention: This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact: The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention: Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact: Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention: This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.


Table name:
Table 4: Clinically Relevant Interactions Affecting Omeprazole When Co-Administered with Other Drugs
CYP2C19 or CYP3A4 Inducers
Clinical Impact:
Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology (12.3)].
Intervention:
St. John’s Wort, rifampin: Avoid concomitant use with omeprazole [see Warnings and Precautions (5.9)].
Ritonavir-containing products: see prescribing information for specific drugs.
CYP2C19 or CYP3A4 Inhibitors
Clinical Impact:
Increased exposure of omeprazole [see Clinical Pharmacology (12.3)].
Intervention:
Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered.
 
See prescribing information for voriconazole.


Table name:
Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme
Inhibitors
Inducers
CYP2C9 
amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast
aprepitant, bosentan, carbamazepine, phenobarbital, rifampin 
CYP1A2 
acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton
montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking 
CYP3A4 
alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton
armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide 


Table name:
Table 3 Clinically Significant Drug Interactions with Meloxicam
Drugs  that  Interfere  with  Hemostasis
Clinical  Impact :
Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.
Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention :
Monitor patients with concomitant use of meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ see  Warnings  and  Precautions  ( 5 . 11)].
Aspirin
Clinical  Impact :
Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ see  Warnings  and  Precautions  ( 5 . 2)].
Intervention :
Concomitant use of meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see  Warnings  and  Precautions  ( 5 . 11)].
Meloxicam is not a substitute for low dose aspirin for cardiovascular protection.
ACE  Inhibitors Angiotensin  Receptor  Blockers or  Beta - Blockers
Clinical  Impact :
NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).
In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, coadministration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention :
During concomitant use of meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.
During concomitant use of meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ see  Warnings  and  Precautions  ( 5 . 6 )].
When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical  Impact :
Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam.
Intervention :
During concomitant use of meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ see  Warnings  and  Precautions  ( 5 . 6)].
Lithium
Clinical  Impact :
NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [ see  Clinical  Pharmacology  ( 12 . 3)].
Intervention :
During concomitant use of meloxicam and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical  Impact :
Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention :
During concomitant use of meloxicam and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical  Impact :
Concomitant use of meloxicam and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention :
During concomitant use of meloxicam and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs  and  Salicylates
Clinical  Impact :
Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ see  Warnings  and  Precautions  ( 5 . 2)].
Intervention :
The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical  Impact :
Concomitant use of meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention :
During concomitant use of meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.
Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended.


Table name:
Table 9: Drugs That are Affected by and Affecting Ciprofloxacin Tablets
Drugs That are Affected by Ciprofloxacin Tablets
Drug(s) Recommendation Comments
Tizanidine Contraindicated Concomitant administration of tizanidine and ciprofloxacin tablets is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)].
Theophylline Avoid use (Plasma exposure likely to be increased and prolonged) Concurrent administration of ciprofloxacin tablets with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions (5.9) ].
Drugs Known to Prolong QT Interval Avoid use Ciprofloxacin tablets may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.11) and Use in Specific Populations (8.5)].
Oral Antidiabetic Drugs Use with caution Glucose-lowering effect potentiated Hypoglycemia sometimes severe has been reported when ciprofloxacin tablets and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were coadministered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin tablets are co-administered with oral antidiabetic drugs [see Adverse Reactions (6.1)].
Phenytoin Use with caution Altered serum levels of phenytoin (increased and decreased) To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin tablets discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin tablets with phenytoin.
Cyclosporine Use with caution (Transient elevations in serum creatinine) Monitor renal function (in particular serum creatinine) when ciprofloxacin tablets are co-administered with cyclosporine.
Anticoagulant Drugs Use with caution (Increase in anticoagulant effect) The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin tablets to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin tablets with an oral anticoagulant (for example, warfarin).
Methotrexate Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin tablets therapy is indicated.
Ropinirole Use with caution Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin tablets [see Warnings and Precautions (5.16) ].
Clozapine Use with caution Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin tablets are advised.
NSAIDs Use with caution Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil Use with caution 2-fold increase in exposure Monitor for sildenafil toxicity [see Clinical Pharmacology (12.3) ].
Duloxetine Avoid use 5-fold increase in duloxetine exposure If unavoidable, monitor for duloxetine toxicity.
Caffeine/Xanthine Derivatives Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life Ciprofloxacin tablets inhibit the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin Tablets
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products) Ciprofloxacin tablets should be taken at least 2 hours before or 6 hours after multivalent cation-containing products administration [see Dosage and Administration (2.4) ]. Decrease ciprofloxacin tablets absorption, resulting in lower serum and urine levels.
Probenecid Use with caution (Interferes with renal tubular secretion of ciprofloxacin tablets and increases ciprofloxacin serum levels) Potentiation of ciprofloxacin tablets toxicity may occur.


Table name:
Table 14: Clinically Important Drug Interactions: Effect of other Drugs on Guanfacine Extended-Release
 Concomitant Drug Name or
Drug Class
 Clinical Rationale and Magnitude of Drug Interaction  Clinical Recommendation
 Strong and moderate CYP3A4 inhibitors, e.g., ketoconazole, fluconazole  Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected
resulting in an increase in exposure
 Consider dose reduction [see Dosage and administration ( 2.7 )]
 Strong and moderate CYP3A4 inducers, e.g., rifampin, efavirenz  Guanfacine is primarily metabolized by CYP3A4 and its
plasma concentrations can be significantly affected resulting in a decrease in exposure
 Consider dose increase
[see Dosage and administration ( 2.7 )]


Table name:
Specific Drugs Reported
also: diet high in vitamin K
        unreliable PT/INR determinations
†Increased and decreased PT/INR responses have been reported.
alcohol†
aminoglutethimide
amobarbital
atorvastatin†
azathioprine
butabarbital
butalbital
carbamazepine
chloral hydrate†
chlordiazepoxide
chlorthalidone
cholestyramine†
clozapine
corticotropin
cortisone
cyclophosphamide†
dicloxacillin
ethchlorvynol
glutethimide
griseofulvin
haloperidol
meprobamate
6-mercaptopurine
methimazole†
moricizine hydrochloride†
nafcillin
paraldehyde
pentobarbital
phenobarbital
phenytoin†
pravastatin†
prednisone†
primidone
propylthiouracil†
raloxifene
ranitidine†
rifampin
secobarbital
spironolactone
sucralfate
trazodone
vitamin C (high dose)
vitamin K
warfarin underdosage


Table name:
Drugs That Interfere with Hemostasis
  Clinical Impact: Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of celecoxib capsules with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ see Warnings and Precautions (5.11) ].
Aspirin
   Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ see Warnings and Precautions (5.2) ]. In two studies in healthy volunteers, and in patients with osteoarthritis and established heart disease respectively, celecoxib (200-400 mg daily) has demonstrated a lack of interference with the cardioprotective antiplatelet effect of aspirin (100-325 mg).
Intervention: Concomitant use of celecoxib capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions (5.11) ]. Celecoxib capsules is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
  Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
   Intervention: During concomitant use of celecoxib capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of celecoxib capsules and ACE-inhibitors or ARBs in patients who are elderly, volume- depleted, or have impaired renal function, monitor for signs of worsening renal function [ see Warnings and Precautions (5.6) ]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of celecoxib capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ see Warnings and Precautions (5.6) ].
Digoxin
Clinical Impact: The concomitant use of celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of celecoxib capsules and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of celecoxib capsules and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Celecoxib capsules have no effect on methotrexate pharmacokinetics.
Intervention: During concomitant use of celecoxib capsules and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of celecoxib capsules and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of celecoxib capsules and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ see Warnings and Precautions (5.2) ].
Intervention: The concomitant use of celecoxib with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of celecoxib capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of celecoxib capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.
NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.
In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
CYP2C9 Inhibitors or inducers
Clinical Impact: Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Co­-administration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of celecoxib.
Intervention Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers. [ see Clinical Pharmacology (12.3) ].
CYP2D6 substrates
Clinical Impact: In vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6 (e.g. atomoxetine), and celecoxib may enhance the exposure and toxicity of these drugs.
Intervention Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2D6 substrates. [ see Clinical Pharmacology (12.3) ].
Corticosteroids
Clinical Impact: Concomitant use of corticosteroids with celecoxib capsules may increase the risk of GI ulceration or bleeding.
Intervention Monitor patients with concomitant use of celecoxib capsules with corticosteroids for signs of bleeding [see Warnings and Precautions (5.2)].


Table name:
Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug Dosing Schedule Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio Change relative to reference) Risperidone Dose Recommendation
Coadministered Drug Risperidone AUC Cmax
Enzyme (CYP2D6) Inhibitors
Fluoxetine 20 mg/day 2 or 3 mg twice daily 1.4 1.5 Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine 10 mg/day 4 mg/day 1.3 - Re-evaluate dosing. Do not exceed 8 mg/day
20 mg/day 4 mg/day 1.6 -
40 mg/day 4 mg/day 1.8 -
Enzyme (CYP3A/PgP inducers) Inducers
Carbamazepine 573 ± 168 mg/day 3 mg twice daily 0.51 0.55 Titrate dose upwards. Do not exceed twice the patient's usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine 150 mg twice daily 1 mg single dose 1.2 1.4 Dose adjustment not needed
Cimetidine 400 mg twice daily 1 mg single dose 1.1 1.3 Dose adjustment not needed
Erythromycin 500 mg four times daily 1 mg single dose 1.1 0.94 Dose adjustment not needed
Other Drugs
Amitriptyline 50 mg twice daily 3 mg twice daily 1.2 1.1 Dose adjustment not needed


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class:
Drug Name
Effect on Concentration of Lopinavir or Concomitant Drug Clinical Comments
HIV-1 Antiviral Agents
HIV-1 Protease Inhibitor:
fosamprenavir/ritonavir
↓ amprenavir
↓ lopinavir
An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor:
indinavir*
↑ indinavir Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily. KALETRA once daily has not been studied in combination with indinavir.
HIV-1 Protease Inhibitor:
nelfinavir*
↑ nelfinavir
↑ M8 metabolite of nelfinavir
↓ lopinavir
KALETRA once daily in combination with nelfinavir is not recommended [see Dosage and Administration ( 2)] .
HIV-1 Protease Inhibitor:
ritonavir*
↑ lopinavir Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor:
saquinavir
↑ saquinavir The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily.
KALETRA once daily has not been studied in combination with saquinavir.
HIV-1 Protease Inhibitor:
tipranavir*
↓ lopinavir Co-administration with tipranavir (500 mg twice daily) and ritonavir (200 mg twice daily) is not recommended.
HIV CCR5 – Antagonist:
maraviroc*
↑ maraviroc When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for maraviroc.
Non-nucleoside Reverse Transcriptase Inhibitors:
efavirenz*,
nevirapine*
↓ lopinavir Increase the dose of KALETRA tablets to 500/125 mg when KALETRA tablet is co-administered with efavirenz or nevirapine. KALETRA once daily in combination with efavirenz or nevirapine is not recommended [see Dosage and Administration ( 2)] .
Non-nucleoside Reverse Transcriptase Inhibitor:
delavirdine
↑ lopinavir Appropriate doses of the combination with respect to safety and efficacy have not been established.
Nucleoside Reverse Transcriptase Inhibitor:
didanosine
  KALETRA tablets can be administered simultaneously with didanosine without food.
For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food).
Nucleoside Reverse Transcriptase Inhibitor:
tenofovir disoproxil fumarate*
↑ tenofovir Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir.
Nucleoside Reverse Transcriptase Inhibitors:
abacavir
zidovudine
↓ abacavir
↓ zidovudine
The clinical significance of this potential interaction is unknown.
Other Agents
Antiarrhythmics e.g.
amiodarone,
bepridil,
lidocaine (systemic),
quinidine
↑ antiarrhythmics For contraindicated antiarrhythmics, [see Contraindications ( 4)] .
Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA.
Anticancer Agents:
vincristine,
vinblastine,
dasatinib,
nilotinib
↑ anticancer agents For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when KALETRA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor.

A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as KALETRA. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions.
Anticoagulants:
warfarin,
rivaroxaban
↑↓ warfarin



↑ rivaroxaban
Concentrations of warfarin may be affected. Initial frequent monitoring of the INR during KALETRA and warfarin co-administration is recommended.

Avoid concomitant use of rivaroxaban and KALETRA. Co-administration of KALETRA and rivaroxaban may lead to increased risk of bleeding.
Anticonvulsants:
carbamazepine,
phenobarbital,
phenytoin
↓ lopinavir
↓ phenytoin
KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution.
KALETRA once daily in combination with carbamazepine, phenobarbital, or phenytoin is not recommended.
In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA.
Anticonvulsants:
lamotrigine,
valproate
↓ lamotrigine
↓ or ↔ valproate
A dose increase of lamotrigine or valproate may be needed when co-administered with KALETRA and therapeutic concentration monitoring for lamotrigine may be indicated; particularly during dosage adjustments.
Antidepressant:
bupropion
↓ bupropion
↓ active metabolite,
hydroxybupropion
Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion.
Antidepressant:
trazodone
↑ trazodone Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. A lower dose of trazodone should be considered.
Anti-infective:
clarithromycin
↑ clarithromycin For patients with renal impairment, adjust clarithromycin dose as follows: For patients on KALETRA with CL CR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients on KALETRA with CL CR < 30 mL/min the dose of clarithromycin should be decreased by 75%. No dose adjustment for patients with normal renal function is necessary.
Antifungals:
ketoconazole*,
itraconazole,
voriconazole
isavuconazonium sulfate*
↑ ketoconazole
↑ itraconazole
↓ voriconazole
↑ isavuconazonium
High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended.
The coadministration of voriconazole and KALETRA should be avoided unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Isavuconazonium and Kaletra should be coadministered with caution. Alternative antifungal therapies should be considered in these patients.
Anti-gout:
colchicine
↑ colchicine Concomitant administration with colchicine is contraindicated in patients with renal and/or hepatic impairment [see Contraindications ( 4)] .

For patients with normal renal or hepatic function:

Treatment of gout flares-co-administration of colchicine in patients on KALETRA:
0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days.

Prophylaxis of gout flares-co-administration of colchicine in patients on KALETRA:
If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.
If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.

Treatment of familial Mediterranean fever (FMF)-co-administration of colchicine in patients on KALETRA:
Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Antimycobacterial:
bedaquiline
↑ bedaquiline For contraindicated antimycobacterials, [see Contraindications ( 4)] .
Bedaquiline should only be used with KALETRA if the benefit of co-administration outweighs the risk.
Antimycobacterial:
rifabutin*
↑ rifabutin and rifabutin metabolite Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary.
Antiparasitic:
atovaquone
↓ atovaquone Clinical significance is unknown; however, increase in atovaquone doses may be needed.
Antipsychotics: quetiapine ↑ quetiapine Initiation of KALETRA in patients taking quetiapine:
Consider alternative antiretroviral therapy to avoid increases in quetiapine exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring.

Initiation of quetiapine in patients taking KALETRA:
Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.
Sedative/hypnotics:
parenterally administered midazolam
↑ midazolam For contraindicated sedative/hypnotics, [see Contraindications ( 4)] .
If KALETRA is co-administered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.
Contraceptive:
ethinyl estradiol*
↓ ethinyl estradiol Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended.
Corticosteroids (systemic): e.g.
budesonide,
dexamethasone,
prednisone
↓ lopinavir
↑ glucocorticoids
Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly.
Concomitant use of glucocorticoids that are metabolized by CYP3A, particularly for long-term use, should consider the potential benefit of treatment versus the risk of systemic corticosteroid effects. Concomitant use may increase the risk for development of systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression.
Dihydropyridine Calcium Channel Blockers: e.g.
felodipine,
nifedipine,
nicardipine
↑ dihydropyridine calcium channel blockers Clinical monitoring of patients is recommended and a dose reduction of the dihydropyridine calcium channel blocker may be considered.
Disulfiram/metronidazole   KALETRA oral solution contains alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).
Endothelin Receptor Antagonists:
bosentan
↑ bosentan Co-administration of bosentan in patients on KALETRA:
In patients who have been receiving KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Co-administration of KALETRA in patients on bosentan:
Discontinue use of bosentan at least 36 hours prior to initiation of KALETRA.
After at least 10 days following the initiation of KALETRA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Hepatitis C direct acting antivirals:
boceprevir*

simeprevir

ombitasvir/parataprevir/
ritonavir and dasabuvir*
↓ lopinavir
↓ boceprevir
↓ ritonavir

↑simeprevir

↑ ombitsavir
↑ parataprevir
↑ ritonavir
↔ dasabuvir
For contraindicated hepatitis C direct acting antivirals, [see Contraindications ( 4)] .
It is not recommended to co-administer KALETRA and boceprevir, simeprevir, or ombitasvir/parataprevir/ritonavir and dasabuvir.
HMG-CoA Reductase Inhibitors:
atorvastatin
rosuvastatin
↑ atorvastatin
↑ rosuvastatin
For contraindicated HMG-CoA reductase inhibitors, [see Contraindications ( 4)] .
Use atorvastatin with caution and at the lowest necessary dose. Titrate rosuvastatin dose carefully and use the lowest necessary dose; do not exceed rosuvastatin 10 mg/day.
Immunosuppressants: e.g.
cyclosporine,
tacrolimus,
sirolimus
↑ immunosuppressants Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA.
Inhaled or Intranasal Steroids e.g.:
fluticasone,
budesonide
↑ glucocorticoids Concomitant use of KALETRA and fluticasone or other glucocorticoids that are metabolized by CYP3A is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects. Concomitant use may result in increased steroid concentrations and reduce serum cortisol concentrations.
Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during postmarketing use in patients when certain ritonavir-containing products have been co-administered with fluticasone propionate or budesonide.
Long-acting beta-adrenoceptor Agonist:
salmeterol
↑ salmeterol Concurrent administration of salmeterol and KALETRA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Narcotic Analgesics:
methadone,*
fentanyl
↓ methadone
↑ fentanyl
Dosage of methadone may need to be increased when co-administered with KALETRA.

Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with KALETRA.
PDE5 inhibitors:
avanafil,
sildenafil,
tadalafil,
vardenafil
↑ avanafil
↑ sildenafil
↑ tadalafil
↑ vardenafil
For contraindicated PDE5 inhibitors, [see Contraindications ( 4)] .
Do not use KALETRA with avanafil because a safe and effective avanafil dosage regimen has not been established.

Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection.

Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH):

Sildenafil (Revatio ®) is contraindicated [see Contraindications ( 4)] .
The following dose adjustments are recommended for use of tadalafil (Adcirca ®) with KALETRA:
Co-administration of ADCIRCA in patients on KALETRA:
In patients receiving KALETRA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Co-administration of KALETRA in patients on ADCIRCA:
Avoid use of ADCIRCA during the initiation of KALETRA. Stop ADCIRCA at least 24 hours prior to starting KALETRA. After at least one week following the initiation of KALETRA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Use of PDE5 inhibitors for erectile dysfunction:

It is recommended not to exceed the following doses:
  • Sildenafil: 25 mg every 48 hours
  • Tadalafil: 10 mg every 72 hours
  • Vardenafil: 2.5 mg every 72 hours
Use with increased monitoring for adverse events.
* see Clinical Pharmacology ( 12.3) for magnitude of interaction.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
 Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)  Avoid atorvastatin
 HIV protease inhibitor (lopinavir plus ritonavir)  Use with caution and lowest dose necessary
 Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)  Do not exceed 20 mg atorvastatin daily
 HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
 Do not exceed 40 mg atorvastatin daily


Table name:
Drug Effect
 
Phenylephrine with prior administration of monoamine oxidase inhibitors (MAOI).
   
 Cardiac pressor response potentiated. May cause acute hypertensive crisis.
 
Phenylephrine with tricyclic anti-depressants.
   
 Pressor response increased.
 
Phenylephrine with ergot alkaloids.
   
 Excessive rise in blood pressure.
 
Phenylephrine with bronchodilator sympathomimetic agents and with epinephrine or other sympathomimetics.
    Tachycardia or other arrhythmias may occur.
 
Phenylephrine with prior administration of propranolol or other β-adrenergic blockers.
    Cardiostimulating effects blocked.
 
Phenylephrine with atropine sulfate.
   
 Reflex bradycardia blocked; pressor response enhanced.
 
Phenylephrine with prior administration of phentolamine or other α-adrenergic blockers.
    Pressor response decreased.
 
Phenylephrine with diet preparations, such as amphetamines or phenylpropanolamine.
    Synergistic adrenergic response.


Table name:
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C Protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
 Table 1: Drugs that may have their plasma concentrations increased by itraconazole
 Drug Class  Contraindicated  Not Recommended  Use with Caution  Comments
    Under no circumstances is the drug to be coadministered with
itraconazole, and up to two weeks after discontinuation of treatment with itraconazole.
  It is recommended that the use of the drug be avoided during and up to two weeks after discontinuation of
treatment with itraconazole, unless the benefits outweigh the potentially increased risks of side effects. If
coadministration cannot be avoided, clinical monitoring for signs or symptoms of increased or prolonged
effects or side effects of the interacting drug is recommended, and its dosage be reduced or interrupted as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured. The label of the coadministered drug should be consulted for information on dose adjustment and adverse effects.
  Careful monitoring is recommended when the drug is coadministered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of the interacting drug, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured. The label of the coadministered drug should be consulted for information on dose adjustment and adverse effects.
 
 Alpha Blockers    tamsulosin    
 Analgesics  methadone     alfentanil,
buprenorphine IV and sublingual,
fentanyl,
oxycodone,
sufentanil
  Methadone: The potential increase in plasma concentrations of methadone when coadministered with Itraconazole Capsules may increase the risk of serious cardiovascular events including QTc prolongation and torsade de pointes.
Fentanyl: The potential increase in plasma concentrations of fentanyl when coadministered with Itraconazole Capsules may increase the risk of potentially fatal respiratory depression.
Sufentanil: No human pharmacokinetic data of an interaction with itraconazole are available. In vitro data suggest that sufentanil is metabolized by CYP3A4 and so potentially increased sufentanil plasma concentrations would be expected when coadministered with Itraconazole Capsules.
 Antiarrhythmics   disopyramide,
dofetilide,
dronedarone,
quinidine
   digoxin   Disopyramide, dofetilide,
dronedarone, quinidine: The potential increase in plasma concentrations of these drugs when coadministered with Itraconazole Capsules may increase the risk of serious cardiovascular events including QTc prolongation.
 Antibacterials   telithromycin, in
subjects with severe
renal impairment or
severe hepatic impairment
 rifabutin  telithromycin Telithromycin: The potential
increase in plasma concentrations of telithromycin in subjects with severe renal impairment or severe hepatic impairment, when coadministered with
Itraconazole Capsulesmay increase the risk of serious cardiovascular events including QT prolongation and torsade de pointes.

Rifabutin: See also under ‘Drugs that may decrease itraconazole   plasma concentrations’
  Anticoagulants and
Antiplatelet Drugs
 ticagrelor apixaban, rivaroxaban   coumarins,
cilostazol,
dabigatran
  Ticagrelor: The potential increase in plasma concentrations of ticagrelor may increase the risk of bleeding.
Coumarins: Itraconazole Capsules may enhance the anticoagulant effect of coumarin-like drugs, such as warfarin.
 Anticonvulsants    carbamazepine     Carbamazepine: In vivo studies have demonstrated an increase in plasma carbamazepine concentrations in subjects concomitantly receiving ketoconazole. Although there are no data regarding the effect of itraconazole on carbamazepine metabolism, because of the similarities between ketoconazole and itraconazole, concomitant administration of Itraconazole Capsules and carbamazepine may inhibit the metabolism of carbamazepine.See also under ‘Drugs that may decrease itraconazole plasma
concentrations’.
 Antidiabetics     repaglinide,saxagliptin
 
Antihelmintics and
Antiprotozoals
     praziquantel  
Antimigraine Drugs ergot alkaloids, such as
dihydroergotamine,
ergometrine
(ergonovine),
ergotamine,
methylergometrine
(methylergonovine)
   eletriptan   Ergot Alkaloids: The potential increase in plasma concentrations of ergot alkaloids when coadministered with
Itraconazole Capsules  may increase the risk of ergotism, ie. a risk for vasospasm potentially leading to cerebral ischemia and/or ischemia of the extremities.
 Antineoplastics  irinotecan axitinib, dabrafenib, dasatinib, ibrutinib, nilotinib, sunitinib,trabectedin
bortezomib, busulphan,  docetaxel,  erlotinib, gefitinib, imatinib,  ixabepilone,  lapatinib,  ponatinib,  trimetrexate,  vinca alkaloids
Irinotecan: The potential increase in plasma concentrations of irinotecan when coadministered with Itraconazole Capsules may increase the risk of potentially fatal adverse events.
Antipsychotics,
Anxiolytics and
Hypnotics
lurasidone,
oral midazolam,
pimozide,
triazolam
  alprazolam,aripiprazole,buspirone,diazepam,haloperidol,midazolam IV,perospirone,quetiapine,ramelteon,risperidone
  Midazolam, triazolam:Coadministration of
Itraconazole Capsules and oral
midazolam, or triazolam may
cause several-fold increases in plasma concentrations of these drugs. This may potentiate and prolong hypnotic and sedative effects, especially with repeated dosing or chronic administration of these agents.
Pimozide: The potential increase in plasma concentrations of pimozide when coadministered with Itraconazole Capsules may increase the risk of serious cardiovascular events including QTc prolongation and torsade de pointes.
 Antivirals     simeprevir maraviroc,indinavir,ritonavir,saquinavir Indinavir, ritonavir: See also under ‘Drugs that may increase itraconazole plasma
concentrations’.
 Beta Blockers      nadolol  
Calcium Channel
Blockers
felodipine,nisoldipine
  other dihydropyridines,verapamil
  Calcium channel blockers can have a negative inotropic effect which may be additive to those of itraconazole. The potential increase in plasma concentrations of calcium channel blockers when
co-administered with Itraconazole Capsules may increase the risk of congestive heart failure.
Dihydropyridines: Concomitant administration of Itraconazole Capsules may cause several-fold increases in plasma concentrations of dihydropyridines. Edema has been reported in patients concomitantly receiving Itraconazole Capsules and
dihydropyridine calcium channel blockers.
Cardiovascular
Drugs, Miscellaneous
Ivabradine,
ranolazine
  aliskiren, sildenafil, for the treatment of pulmonary hypertension
  bosentan, riociguat
Ivabradine: The potential increase in plasma concentrations of ivabradine when coadministered with Itraconazole Capsules may increase the risk of ivabradine-related adverse events, such as atrial fibrillation, bradycardia, sinus arrest and heart block. 
Ranolazine: The potential
increase in plasma concentrations of ranolazine when coadministered with
Itraconazole Capsules may increase the risk of serious cardiovascular events including QTc prolongation.
 Diuretics  eplerenone     Eplerenone: The potential
increase in plasma concentrations f eplerenone when coadministered with
Itraconazole Capsules  may increase the risk of hyperkalemia and hypotension.
Gastrointestinal
Drugs
 cisapride    aprepitant   Cisapride: The potential increase in plasma concentrations of
cisapride when oadministered
with Itraconazole Capsules may increase the risk of serious cardiovascular events including QTc prolongation.
 Immunosuppressants   everolimus,
temsirolimus
budesonide,ciclesonide,cyclosporine,dexamethasone,fluticasone,methylprednisolone,rapamycin (also known as sirolimus),tacrolimus
 
Lipid Regulating
Drugs
lovastatin,
simvastatin
   atorvastatin The potential increase in plasma concentrations of atorvastatin,lovastatin, and simvastatin when coadministered with Itraconazole Capsules may increase the risk of skeletal muscle toxicity,including rhabdomyolysis.
 Respiratory Drugs    salmeterol    
 Urological Drugs   fesoterodine, in subjects with moderate to severe renal impairment, or moderate to severe hepatic impairment, solifenacin, in subjects with severe renal impairment or moderate to severe hepatic impairment
  darifenacin, vardenafil
Fesoterodine, oxybutynin,  sildenafil, for the treatment of erectile dysfunction, solifenacin, tadalafil, tolterodine
 
 
  Fesoterodine: The potential increase in plasma concentrations of the fesoterodine active metabolite may be greater in subjects with moderate to severe renal impairment, or moderate to severe hepatic impairment, which may lead to an increased risk of adverse reactions.
Solifenacin: The potential increase in plasma concentrations of solifenacin in subjects with severe renal impairment or moderate to severe hepatic impairment, when coadministered with Itraconazole Capsules may increase the risk of serious cardiovascular events including QT prolongation.
 Other colchicine, in subjects
with renal or hepatic
impairment
  colchicines, conivaptan, tolvaptan
cinacalcet,
Colchicine: The potential increase in plasma concentrations of
colchicine when coadministered
with Itraconazole Capsules may increase the risk of potentially fatal adverse
events.


Conivaptan and Tolvaptan: A safe and effective dose of either conivaptan or tolvaptan has not been established when coadministered with Itraconazole Capsules.
 
 


Table name:
Table 3 Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table 4 for Magnitude of Interaction.
Drug Name Effect on Concentration of Nevirapine or Concomitant Drug Clinical Comment
HIV Antiviral Agents: Protease Inhibitors (PIs)
Atazanavir/Ritonavir* ↓ Atazanavir
↑ Nevirapine
Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures.
Fosamprenavir*


Fosamprenavir/Ritonavir*
↓ Amprenavir
↑ Nevirapine

↓ Amprenavir
↑ Nevirapine
Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.


No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied.
Indinavir* ↓ Indinavir The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established.
Lopinavir/Ritonavir* ↓Lopinavir Dosing in adult patients:
A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.

Dosing in pediatric patients:
Please refer to the Kaletra® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.
Nelfinavir* ↓Nelfinavir M8 Metabolite
↓Nelfinavir Cmin
The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established.
Saquinavir/ritonavir The interaction between Nevirapine and saquinavir/ritonavir has not been evaluated The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz*



Delavirdine
Etravirine
Rilpivirine
↓ Efavirenz The appropriate doses of these combinations with respect to safety and efficacy have not been established.




Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial.
Other Agents
Analgesics:
Methadone*
↓ Methadone Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Antiarrhythmics: Amiodarone, disopyramide, lidocaine Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Antibiotics:
Clarithromycin* 




Rifabutin*





Rifampin*
↓ Clarithromycin
↑ 14-OH clarithromycin 




↑ Rifabutin





↓ Nevirapine
Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.


Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.




Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Anticonvulsants:
Carbamazepine, clonazepam, ethosuximide
Plasma concentrations of nevirapine and the anticonvulsant may be decreased. Use with caution and monitor virologic response and levels of anticonvulsants.
Antifungals:
Fluconazole*


Ketoconazole*



Itraconazole
↑Nevirapine



↓ Ketoconazole



↓ Itraconazole
Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events.


Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.



Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug.
Antithrombotics:
Warfarin
Plasma concentrations may be increased. Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.
Calcium channel blockers: Diltiazem, nifedipine, verapamil Plasma concentrations may be decreased. Appropriate doses for these combinations have not been established.
Cancer chemotherapy: Cyclophosphamide Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Ergot alkaloids: Ergotamine Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Immunosuppressants: Cyclosporine, tacrolimus, sirolimus Plasma concentrations may be decreased. Appropriate doses for these combinations have not been established.
Motility agents: Cisapride Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Opiate agonists: Fentanyl Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Oral contraceptives:
Ethinyl estradiol and Norethindrone*
↓ Ethinyl estradiol
↓ Norethindrone
Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended.
* The interaction between Nevirapine and the drug was evaluated in a clinical study. All other drug interactions shown are predicted.


Table name:
Table 3Drugs that Can Increase the Risk of Bleeding
Drug  Class
Specific  Drugs
Anticoagulants 
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin 
Antiplatelet Agents 
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine 
Nonsteroidal Anti-Inflammatory Agents 
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac 
Serotonin Reuptake Inhibitors 
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone 


Table name:
Table 3:   Drugs that Can Increase the Risk of Bleeding
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
Interacting Drug Interaction
Theophylline Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin Monitor phenytoin level (7)
Methotrexate Monitor for methotrexate toxicity (7)
Cyclosporine May increase serum creatinine. Monitor serum creatinine (7)
Multivalent cation-containing products including antacids, metal cations or didanosine Decreased Ciprofloxacin Tablets, USP absorption. Take 2 hours before or 6 hours after Ciprofloxacin Tablets, USP (7)


Table name:
Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) VIAGRA 100 mg
Supine 7.9 (4.6, 11.1)
Standing

4.3 (-1.8,10.3)



Table name:
 Digoxin concentrations increased greater than 50%
        Digoxin Serum     
Concentration
Increase
      Digoxin AUC     
Increase
 Recommendations
 Quinidine  NA   54-83% Measure serum digoxin concentrations before     
initiating concomitant drugs. Reduce digoxin
concentrations by decreasing dose by
approximately 30-50% or by modifying the
dosing frequency and continue monitoring.
 Ritonavir  NA  86%
 Digoxin concentrations increased less than 50%
 Amiodarone  17%  40% Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring.
 Propafenone  28%  29%
 Quinine  NA  34-38%
 Spironolactone       NA  44%
 Verapamil  NA  24%


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Specific Drugs Reported
also: diet high in vitamin K
unreliable PT/INR determinations
†Increased and decreased PT/INR responses have been reported.
alcohol†
aminoglutethimide
amobarbital
atorvastatin†
azathioprine
butabarbital
butalbital
carbamazepine
chloral hydrate†
chlordiazepoxide
chlorthalidone
cholestyramine†
clozapine
corticotropin
cortisone
cyclophosphamide†
dicloxacillin
ethchlorvynol
glutethimide
griseofulvin
haloperidol
meprobamate
6-mercaptopurine
methimazole†
moricizine hydrochloride†
nafcillin
paraldehyde
pentobarbital
phenobarbital
phenytoin†
pravastatin†
prednisone†
primidone
propylthiouracil†
raloxifene
ranitidine†
rifampin
secobarbital
spironolactone
sucralfate
trazodone
vitamin C (high dose)
vitamin K
warfarin underdosage


Table name:
Factors Dosage Adjustments for Aripiprazole
Known CYP2D6 Poor Metabolizers Administer half of usual dose  
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors Administer half of usual dose
Strong CYP2D6 and CYP3A4 inhibitors Administer a quarter of usual dose
Strong CYP3A4 inducers Double usual dose over 1 to 2 weeks


Table name:
Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Calcium Channel Blockers Antifungals Antibiotics Glucocorticoids Other Drugs
diltiazem fluconazole azithromycin methylprednisolone allopurinol
nicardipine itraconazole clarithromycin amiodarone
verapamil ketoconazole erythromycin bromocriptine
voriconazole quinupristin/dalfopristin colchicine
danazol
imatinib
metoclopramide
nefazodone
oral contraceptives


Table name:
Calcium Channel Blockers Antifungals Antibiotics Glucocorticoids Other Drugs                   
diltiazem fluconazole azithromycin methylprednisolone     allopurinol                           
nicardipine itraconazole clarithromycin amiodarone
verapamil ketoconazole erythromycin bromocriptine
quinupristin/ colchicine
voriconazole dalfopristin danazol
imatinib
metoclopramide
nefazodone
oral contraceptives


Table name:
Table 2: Clinically Significant Drug Interactions with Oxaprozin Drugs That Interfere with Hemostasis
Clinical Impact: Oxaprozin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of oxaprozin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of oxaprozin with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11 )].
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].
Intervention: Concomitant use of oxaprozin and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. Oxaprozin is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: During concomitant use of oxaprozin and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of oxaprozin and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of oxaprozin with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)]. 
Digoxin
Clinical Impact: The concomitant use of oxaprozin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of oxaprozin and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of oxaprozin and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction) because NSAID administration may result in increased plasma levels of methotrexate, especially in patients receiving high doses of methotrexate.
Intervention: During concomitant use of oxaprozin and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of oxaprozin and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of oxaprozin and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of oxaprozin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention: The concomitant use of oxaprozin with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of oxaprozin and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of oxaprozin and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Corticosteroids  
Clinical Impact: Concomitant use of corticosteroids with oxaprozin may increase the risk of GI ulceration or bleeding.
Intervention: Monitor patients with concomitant use of oxaprozin with corticosteroids for signs of bleeding [see Warnings and Precautions (5.2)].
Glyburide  
Clinical Impact: While oxaprozin does alter the pharmacokinetics of glyburide, coadministration of oxaprozin to type II non-insulin dependent diabetic patients did not affect the area under the glucose concentration curve nor the magnitude or duration of control.
Intervention: During concomitant use of oxaprozin and glyburide, monitor patient’s blood glucose in the beginning phase of cotherapy.


Table name:
Table II. Clinically significant drug interactions with theophylline*.
* Refer to PRECAUTIONS, Drug Interactions for further information regarding table.
** Average effect on steady state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.
DrugType of InteractionEffect**
Adenosine Theophylline blocks adenosine receptors. Higher doses of adenosine may be required to achieve desired effect.
Alcohol A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours. 30% increase
Allopurinol Decreases theophylline clearance at allopurinol doses ≥ 600 mg/day. 25% increase
Aminoglutethimide Increases theophylline clearance by induction of microsomal enzyme activity. 25% decrease
CarbamazepineSimilar to aminoglutethimide. 30% decrease
CimetidineDecreases theophylline clearance by inhibiting cytochrome P450 1A2. 70% increase
CiprofloxacinSimilar to cimetidine.40% increase
ClarithromycinSimilar to erythromycin.25% increase
DiazepamBenzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant while theophylline blocks adenosine receptors.Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram Decreases theophylline clearance by inhibiting hydroxylation and demethylation. 50% increase
EnoxacinSimilar to cimetidine. 300% increase
Ephedrine Synergistic CNS effects Increased frequency of nausea, nervousness, and insomnia.
ErythromycinErythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3.  35% increase
Erythromycin steady-state serum concentrations decrease by a similar amount.
EstrogenEstrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown. 30% increase
FlurazepamSimilar to diazepam.Similar to diazepam.
FluvoxamineSimilar to cimetidineSimilar to cimetidine
Halothane Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines. Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-ADecreases theophylline clearance. 100% increase
Isoproterenol (IV)Increases theophylline clearance.20% decrease
KetaminePharmacologicMay lower theophylline seizure threshold.
Lithium Theophylline increases renal lithium clearance. Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam Similar to diazepam. Similar to diazepam.
Methotrexate (MTX) Decreases theophylline clearance20% increase after low dose MTX, higher dose MTX may have a greater effect.
MexiletineSimilar to disulfiram.80% increase
MidazolamSimilar to diazepam.Similar to diazepam.
MoricizineIncreases theophylline clearance.25% decrease
Pancuronium Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to  phosphodiesterase inhibition. Larger dose of pancuronium may be required to achieve neuromuscular blockade.
PentoxifyllineDecreases theophylline clearance.30% increase
Phenobarbital (PB)Similar to aminoglutethimide.25% decrease after two weeks of concurrent PB.
Phenytoin Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Serum theophylline and phenytoin concentrations decrease about 40%.
Theophylline decreases phenytoin absorption.
PropafenoneDecreases theophylline clearance and pharmacologic interaction.40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
PropranololSimilar to cimetidine and pharmacologic interaction.100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Rifampin Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity. 20-40% decrease
Sulfinpyrazone Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline. 20% decrease
TacrineSimilar to cimetidine, also increases renal clearance of theophylline. 90% increase
ThiabendazoleDecreases theophylline clearance.190% increase
TiclopidineDecreases theophylline clearance.60% increase
TroleandomycinSimilar to erythromycin.33-100% increase depending on troleandomycin dose.
Verapamil Similar to disulfiram. 20% increase


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
↓ = Decreased (induces lamotrigine glucuronidation).
↑ = Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
Concomitant Drug 
Effect on Concentration of 
Lamotrigine or Concomitant Drug 
Clinical Comment 
Estrogen-containing oral 
contraceptive 
preparations containing 30 mcg 
ethinylestradiol and 150 mcg levonorgestrel 
↓ lamotrigine 

↓ levonorgestrel 
Decreased lamotrigine concentrations approximately 50%. 

Decrease in levonorgestrel component by 19%. 
Carbamazepine and carbamazepine epoxide 
↓ lamotrigine 


? carbamazepine epoxide 
Addition of carbamazepine decreases 
lamotrigine concentration approximately 40%. 
May increase carbamazepine epoxide levels. 
Lopinavir/ritonavir 
↓ lamotrigine 
Decreased lamotrigine concentration approximately 50%. 
Atazanavir/ritonavir 
↓ lamotrigine
Decreased lamotrigine AUC approximately 32%. 
Phenobarbital/Primidone 
↓ lamotrigine 
Decreased lamotrigine concentration
 approximately 40%. 
Phenytoin 
↓ lamotrigine 
Decreased lamotrigine concentration 
approximately 40%. 
Rifampin 
↓ lamotrigine 
Decreased lamotrigine AUC 
approximately 40%. 
Valproate 
↑ lamotrigine

 ? valproate 
Increased lamotrigine concentrations 
slightly more than 2-fold. 
There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.


Table name:
Bleeding times
Clinical Impact: Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention: This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact: The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention: Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact: Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention: This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.


Table name:
Table 2: Clinically Significant Drug Interactions with CONZIP
Inhibitors of CYP2D6
Clinical Impact: The concomitant use of CONZIP and CYP2D6 inhibitors may result in an increase in the plasma concentration of tramadol and a decrease in the plasma concentration of M1, particularly when an inhibitor is added after a stable dose of CONZIP is achieved. Since M1 is a more potent μ-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome.

After stopping a CYP2D6 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease and the M1 plasma concentration will increase which could increase or prolong therapeutic effects but also increase adverse reactions related to opioid toxicity, and may cause potentially fatal respiratory depression [see Clinical Pharmacology (12.3)].
Intervention: If concomitant use of a CYP2D6 inhibitor is necessary, follow patients closely for adverse reactions including opioid withdrawal, seizures, and serotonin syndrome.

If a CYP2D6 inhibitor is discontinued, consider lowering CONZIP dosage until stable drug effects are achieved. Follow patients closely for adverse events including respiratory depression and sedation.
Examples Quinidine, fluoxetine, paroxetine and bupropion
Inhibitors of CYP3A4
Clinical Impact: The concomitant use of CONZIP and CYP3A4 inhibitors can increase the plasma concentration of tramadol and may result in a greater amount of metabolism via CYP2D6 and greater levels of M1. Follow patients closely for increased risk of serious adverse events including seizures and serotonin syndrome, and adverse reactions related to opioid toxicity including potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of CONZIP is achieved.

After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy and possibly signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol.
Intervention: If concomitant use is necessary, consider dosage reduction of CONZIP until stable drug effects are achieved. Follow patients closely for seizures and serotonin syndrome, and signs of respiratory depression and sedation at frequent intervals.
If a CYP3A4 inhibitor is discontinued, consider increasing the CONZIP dosage until stable drug effects are achieved and follow patients for signs and symptoms of opioid withdrawal.
Examples Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)
CYP3A4 Inducers
Clinical Impact: The concomitant use of CONZIP and CYP3A4 inducers can decrease the plasma concentration of tramadol, [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to tramadol, [see Warnings and Precautions (5.4)].

After stopping a CYP3A4 inducer, as the effects of the inducer decline, the tramadol plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause seizures and serotonin syndrome, and potentially fatal respiratory depression .
Intervention: If concomitant use is necessary, consider increasing the CONZIP dosage until stable drug effects are achieved. Follow patients for signs of opioid withdrawal.
If a CYP3A4 inducer is discontinued, consider CONZIP dosage reduction and monitor for seizures and serotonin syndrome, and signs of sedation and respiratory depression.

Patients taking carbamazepine, a CYP3A4 inducer, may have a significantly reduced analgesic effect of tramadol. Because carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of CONZIP and carbamazepine is not recommended.
Examples: Rifampin, carbamazepine, phenytoin
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.5)].
Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, , antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue CONZIP if serotonin syndrome is suspected.
Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome [see Warnings and Precautions (5.7)] or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)].
Intervention: Do not use CONZIP in patients taking MAOIs or within 14 days of stopping such treatment.
Examples: phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact: May reduce the analgesic effect of CONZIP and/or precipitate withdrawal symptoms.
Intervention: Avoid concomitant use.
Examples: butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact: Tramadol may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of CONZIP and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when CONZIP is used concomitantly with anticholinergic drugs.
Digoxin
Clinical Impact: Post-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity.
Intervention: Follow patients for signs of digoxin toxicity and adjust dosage of digoxin as needed.
Warfarin
Clinical Impact: Post-marketing surveillance of tramadol has revealed rare reports of alteration of warfarin effect, including elevation of prothrombin times.
Intervention: Monitor the prothrombin time of patients on warfarin for signs of an interaction and adjust the dosage of warfarin as needed.


Table name:
Figure 1: Effect of interacting drugs on the pharmacokinetics of venlafaxine and active metabolite O-desmethylvenlafaxine (ODV).


Table name:
a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
b = Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated
AED Co-administered 
AED Concentration
Topiramate Concentration
Phenytoin 
NC or 25% increasea
48% decrease
Carbamazepine (CBZ)
NC 
40% decrease
CBZ epoxideb
NC
NE
Valproic acid 
11% decrease
14% decrease
Phenobarbital
NC
NE
Primidone 
NC
NE
Lamotrigine 
NC at TPM doses up to 400 mg/day
13% decrease


Table name:
Table 2: Clinically Significant Drug Interactions with mefenamic acid
Drugs That Interfere with Hemostasis
Clinical Impact: Mefenamic acid and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of mefenamic acid and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of mefenamic acid with anticoagulants (e.g.,warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity ).
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation ).
Intervention: Concomitant use of mefenamic acid and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity ).
Mefenamic acid is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: During concomitant use of mefenamic acid and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of mefenamic acid and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia ). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of mefenamic acid with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia ).
Digoxin
Clinical Impact: The concomitant use of mefenamic acid with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of mefenamic acid and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of mefenamic acid and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of mefenamic acid and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of mefenamic acid and cyclosporine may increase cyclosporine's nephrotoxicity.
Intervention: During concomitant use of mefenamic acid and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of mefenamic acid with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation ).
Intervention: The concomitant use of mefenamic acid with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of mefenamic acid and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of mefenamic acid and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.
NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.
In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacid
Clinical Impact: In a single dose study (n=6), ingestion of an antacid containing 1.7-gram of magnesium hydroxide with 500-mg of mefenamic acid increased the Cmax and AUC of mefenamic acid by 125% and 36%, respectively.
Intervention: Concomitant use of mefenamic acid and antacids is not generally recommended because of possible increased adverse events.


Table name:
Antibiotics Antineoplastics Antifungals Anti-inflammatory Drugs Gastrointestinal Agents Immunosuppressives Other Drugs
ciprofloxacin melphalan   amphotericin B azapropazon cimetidine tacrolimus fibric acid derivatives (e.g., bezafibrate, fenofibrate)
gentamicin ketoconazole colchicine ranitidine  methotrexate
tobramycin diclofenac
vancomycin naproxen
trimethoprim with sulfamethoxazole sulindac


Table name:
Table 4: Clinically Relevant Interactions Affecting Omeprazole When Co-Administered with Other Drugs
CYP2C19 or CYP3A4 Inducers
Clinical Impact:
Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology (12.3)].
Intervention:
St. John’s Wort, rifampin: Avoid concomitant use with omeprazole [see Warnings and Precautions (5.9)].
Ritonavir-containing products: see prescribing information for specific drugs.
CYP2C19 or CYP3A4 Inhibitors
Clinical Impact:
Increased exposure of omeprazole [see Clinical Pharmacology (12.3)].
Intervention:
Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered.
 
See prescribing information for voriconazole.


Table name:
Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) VIAGRA 50 mg (95% CI)
Supine 9.08 (5.48, 12.68)
Standing

11.62 (7.34, 15.90)



Table name:
AED  Co - administered
AED  Concentration
Topiramate  Concentration
Phenytoin
NCor25%increase a
48%decrease
Carbamazepine(CBZ)
NC
40%decrease
CBZepoxide b
NC 
            NE
Valproic acid
11%decrease
14%decrease
Phenobarbital
NC
            NE
Primidone
NC
           NE
Lamotrigine
NCatTPM dosesupto400  mg/day 
         13%decrease


Table name:
Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme
Inhibitors
Inducers
CYP2C9 
amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast
aprepitant, bosentan, carbamazepine, phenobarbital, rifampin 
CYP1A2 
acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton
montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking 
CYP3A4 
alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton
armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide 


Table name:
Drug Interactions Associated with Increased Risk of  Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
 Interacting Agents  Prescribing Recommendations
  Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol  Contraindicated with simvastatin
 Verapamil, diltiazem, dronedarone  Do not exceed 10 mg simvastatin daily
 Amiodarone, amlodipine, ranolazine  Do not exceed 20 mg simvastatin daily
 Lomitapide  For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
 Grapefruit juice  Avoid grapefruit juice


Table name:
Drugs that Affect Renal Function A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDS], COX-2 inhibitors may impair the excretion of digoxin.
Antiarrthymics Dofetilide Concomitant administration with digoxin was associated with a higher rate of torsades de pointes
Sotalol Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
Dronedarone Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone Analog Teriparatide Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement Thyroid Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics Epinephrine
Norepinephrine     
Dopamine
Can increase the risk of cardiac arrhythmias
Neuromuscular Blocking Agents      Succinylcholine May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.
Supplements Calcium If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.


Table name:
Strong CYP3A4 Inhibitors
Clinical Impact: Concomitant use of REXULTI with strong CYP3A4 inhibitors increased the exposure of brexpiprazole compared to the use of REXULTI alone [see Clinical Pharmacology (12.3)]
Intervention: With concomitant use of REXULTI with a strong CYP3A4 inhibitor, reduce the REXULTI dosage [see Dosage and Administration (2.5)]
Examples: itraconazole, clarithromycin, ketoconazole
Strong CYP2D6 Inhibitors*
Clinical Impact: Concomitant use of REXULTI with strong CYP2D6 inhibitors increased the exposure of brexpiprazole compared to the use of REXULTI alone [see Clinical Pharmacology (12.3)]
Intervention: With concomitant use of REXULTI with a strong CYP2D6 inhibitor, reduce the REXULTI dosage [see Dosage and Administration (2.5)]
Examples: paroxetine, fluoxetine, quinidine
Both CYP3A4 Inhibitors and CYP2D6 Inhibitors
Clinical Impact: Concomitant use of REXULTI with 1) a strong CYP3A4 inhibitor and a strong CYP2D6 inhibitor; or 2) a moderate CYP3A4 inhibitor and a strong CYP2D6 inhibitor; or 3) a strong CYP3A4 inhibitor and a moderate CYP2D6 inhibitor; or 4) a moderate CYP3A4 inhibitor and a moderate CYP2D6 inhibitor, increased the exposure of brexpiprazole compared to the use of REXULTI alone [see Clinical Pharmacology (12.3)]
Intervention: With concomitant use of REXULTI with 1) a strong CYP3A4 inhibitor and a strong CYP2D6 inhibitor; or 2) a moderate CYP3A4 inhibitor and a strong CYP2D6 inhibitor; or 3) a strong CYP3A4 inhibitor and a moderate CYP2D6 inhibitor; or 4) a moderate CYP3A4 inhibitor and a moderate CYP2D6 inhibitor, decrease the REXULTI dosage [see Dosage and Administration (2.5)]
Examples: 1) itraconazole + quinidine 2) fluconazole + paroxetine 3) itraconazole + duloxetine 4) fluconazole + duloxetine
Strong CYP3A4 Inducers
Clinical Impact: Concomitant use of REXULTI and a strong CYP3A4 inducer decreased the exposure of brexpiprazole compared to the use of REXULTI alone [see Clinical Pharmacology (12.3)]
Intervention: With concomitant use of REXULTI with a strong CYP3A4 inducer, increase the REXULTI dosage [see Dosage and Administration (2.5)]
Examples: rifampin, St. John’s wort


Table name: Use of sildenafil (REVATIO) is contraindicated when used for the treatment of PAH [see Contraindications (4)]. The following dose adjustments are recommended for use of tadalafil (ADCIRCA®) with LEXIVA: Coadministration of ADCIRCA in patients on LEXIVA: In patients receiving LEXIVA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Coadministration of LEXIVA in patients on ADCIRCA: Avoid use of ADCIRCA during the initiation of LEXIVA. Stop ADCIRCA at least 24 hours prior to starting LEXIVA. After at least one week following the initiation of LEXIVA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: LEXIVA: Sildenafil: 25 mg every 48 hours. Tadalafil: no more than 10 mg every 72 hours. Vardenafil: no more than 2.5 mg every 24 hours. LEXIVA/ritonavir: Sildenafil: 25 mg every 48 hours.Tadalafil: no more than 10 mg every 72 hours.Vardenafil: no more than 2.5 mg every 72 hours.Use with increased monitoring for adverse events.
Table 7. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class: Drug Name Effect on Concentration of Amprenavir or Concomitant Drug Clinical Comment
HCV/HIV-Antiviral Agents
HCV protease inhibitor: Boceprevir LEXIVA: ↓Amprenavir (predicted) ↔ or ↓Boceprevir (predicted) LEXIVA/ritonavir: ↓Amprenavir (predicted) ↓Boceprevir (predicted) Coadministration of LEXIVA or LEXIVA/ritonavir and boceprevir is not recommended.
HCV protease inhibitor: Simeprevir LEXIVA: ↔Amprenavir (predicted) ↑ or ↓Simeprevir (predicted) LEXIVA/ritonavir: ↔Amprenavir (predicted) ↑Simeprevir (predicted) Coadministration of LEXIVA or LEXIVA/ritonavir and simeprevir is not recommended.
HCV protease inhibitor: Paritaprevir (coformulated with ritonavir and ombitasvir and coadministered with dasabuvir) LEXIVA: ↑Amprenavir (predicted) ↑ or ↔Paritaprevir (predicted) LEXIVA/ritonavir: ↑ or ↔Amprenavir (predicted) ↑Paritaprevir (predicted) Appropriate doses of the combinations with respect to safety and efficacy have not been established. LEXIVA 1400 mg once daily may be considered when coadministered with paritaprevir/ritonavir/ombitasvir/ dasabuvir. Coadministration of LEXIVA/ritonavir and paritaprevir/ritonavir/ombitasvir/ dasabuvir is not recommended.
Non-nucleoside reverse transcriptase inhibitor: Efavirenza LEXIVA: ↓Amprenavir LEXIVA/ritonavir: ↓Amprenavir Appropriate doses of the combinations with respect to safety and efficacy have not been established. An additional 100 mg/day (300 mg total) of ritonavir is recommended when efavirenz is administered with LEXIVA/ritonavir once daily. No change in the ritonavir dose is required when efavirenz is administered with LEXIVA plus ritonavir twice daily.
Non-nucleoside reverse transcriptase inhibitor: Nevirapinea LEXIVA: ↓Amprenavir ↑Nevirapine LEXIVA/ritonavir: ↓Amprenavir ↑Nevirapine Coadministration of nevirapine and LEXIVA without ritonavir is not recommended. No dosage adjustment required when nevirapine is administered with LEXIVA/ritonavir twice daily. The combination of nevirapine administered with LEXIVA/ritonavir once-daily regimen has not been studied.
HIV protease inhibitor: Atazanavira LEXIVA: Interaction has not been evaluated. LEXIVA/ritonavir: ↓Atazanavir ↔Amprenavir Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV protease inhibitors: Indinavira, nelfinavira LEXIVA: ↑Amprenavir Effect on indinavir and nelfinavir is not well established. LEXIVA/ritonavir: Interaction has not been evaluated. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV protease inhibitors: Lopinavir/ritonavira ↓Amprenavir ↓Lopinavir An increased rate of adverse events has been observed. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV protease inhibitor: Saquinavira LEXIVA: ↓Amprenavir Effect on saquinavir is not well established. LEXIVA/ritonavir: Interaction has not been evaluated. Appropriate doses of the combination with respect to safety and efficacy have not been established.
HIV integrase inhibitor: Raltegravira LEXIVA: ↓Amprenavir ↓Raltegravir LEXIVA/ritonavir: ↓Amprenavir ↓Raltegravir Appropriate doses of the combination with respect to safety and efficacy have not been established.
HIV integrase inhibitor: Dolutegravira LEXIVA/ritonavir: ↓Dolutegravir The recommended dose of dolutegravir is 50 mg twice daily when coadministered with LEXIVA/ritonavir. Use an alternative combination where possible in patients with known or suspected integrase inhibitor resistance.
HIV CCR5 co-receptor antagonist: Maraviroca LEXIVA/ritonavir: ↓Amprenavir ↑Maraviroc No dosage adjustment required for LEXIVA/ritonavir. The recommended dose of maraviroc is 150 mg twice daily when coadministered with LEXIVA/ritonavir. LEXIVA should be given with ritonavir when coadministered with maraviroc.
Other Agents
Antiarrhythmics: Amiodarone, lidocaine (systemic), and quinidine ↑Antiarrhythmics Use with caution. Increased exposure may be associated with life-threatening reactions such as cardiac arrhythmias. Therapeutic concentration monitoring, if available, is recommended for antiarrhythmics.
Anticoagulant: Warfarin Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants: Carbamazepine, phenobarbital, phenytoin Phenytoina LEXIVA: ↓Amprenavir LEXIVA/ritonavir: ↑Amprenavir ↓Phenytoin Use with caution. LEXIVA may be less effective due to decreased amprenavir plasma concentrations in patients taking these agents concomitantly. Plasma phenytoin concentrations should be monitored and phenytoin dose should be increased as appropriate. No change in LEXIVA/ritonavir dose is recommended.
Antidepressant: Paroxetine, trazodone ↓Paroxetine ↑Trazodone Any paroxetine dose adjustment should be guided by clinical effect (tolerability and efficacy). Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as LEXIVA, the combination should be used with caution and a lower dose of trazodone should be considered.
Antifungals: Ketoconazolea, itraconazole ↑Ketoconazole ↑Itraconazole Increase monitoring for adverse events. LEXIVA: Dose reduction of ketoconazole or itraconazole may be needed for patients receiving more than 400 mg ketoconazole or itraconazole per day. LEXIVA/ritonavir: High doses of ketoconazole or itraconazole (greater than 200 mg/day) are not recommended.
Anti-gout: Colchicine ↑Colchicine Patients with renal or hepatic impairment should not be given colchicine with LEXIVA/ritonavir. LEXIVA/ritonavir and coadministration of colchicine: Treatment of gout flares: 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.
If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.
Treatment of familial Mediterranean fever (FMF): Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). LEXIVA and coadministration of colchicine: Treatment of gout flares: 1.2 mg (2 tablets) x 1 dose. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg twice a day or 0.6 mg once a day.
If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once a day.
Treatment of FMF: Maximum daily dose of 1.2 mg (may be given as 0.6 mg twice a day).
Antimycobacterial: Rifabutina ↑Rifabutin and rifabutin metabolite A complete blood count should be performed weekly and as clinically indicated to monitor for neutropenia. LEXIVA: A dosage reduction of rifabutin by at least half the recommended dose is required. LEXIVA/ritonavir: Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (a maximum dose of 150 mg every other day or 3 times per week).
Antipsychotics: Quetiapine LEXIVA/ritonavir: ↑Quetiapine Initiation of LEXIVA with ritonavir in patients taking quetiapine: Consider alternative antiretroviral therapy to avoid increases in quetiapine drug exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring. Initiation of quetiapine in patients taking LEXIVA with ritonavir: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.
Lurasidone ↑Lurasidone LEXIVA: If coadministration is necessary, reduce the lurasidone dose. Refer to the lurasidone prescribing information for concomitant use with moderate CYP3A4 inhibitors. LEXIVA/ritonavir: Use of lurasidone is contraindicated.
Benzodiazepines: Alprazolam, clorazepate, diazepam, flurazepam ↑Benzodiazepines Clinical significance is unknown. A decrease in benzodiazepine dose may be needed.
Calcium channel blockers: Diltiazem, felodipine, nifedipine, nicardipine, nimodipine, verapamil, amlodipine, nisoldipine, isradipine ↑Calcium channel blockers Use with caution. Clinical monitoring of patients is recommended.
Corticosteroid: Dexamethasone ↓Amprenavir Use with caution. LEXIVA may be less effective due to decreased amprenavir plasma concentrations.
Endothelin-receptor antagonists: Bosentan ↑Bosentan Coadministration of bosentan in patients on LEXIVA: In patients who have been receiving LEXIVA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Coadministration of LEXIVA in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of LEXIVA. After at least 10 days following the initiation of LEXIVA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Histamine H2-receptor antagonists: Cimetidine, famotidine, nizatidine, ranitidinea LEXIVA: ↓Amprenavir LEXIVA/ritonavir: Interaction not evaluated Use with caution. LEXIVA may be less effective due to decreased amprenavir plasma concentrations.
HMG-CoA reductase inhibitors: Atorvastatina ↑Atorvastatin Titrate atorvastatin dose carefully and use the lowest necessary dose; do not exceed atorvastatin 20 mg/day.
Immunosuppressants: Cyclosporine, tacrolimus, sirolimus ↑Immunosuppressants Therapeutic concentration monitoring is recommended for immunosuppressant agents.
Inhaled beta-agonist: Salmeterol ↑Salmeterol Concurrent administration of salmeterol with LEXIVA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.
Inhaled/nasal steroid: Fluticasone LEXIVA: ↑Fluticasone LEXIVA/ritonavir: ↑Fluticasone Use with caution. Consider alternatives to fluticasone, particularly for long-term use. May result in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression have been reported during postmarketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone. Coadministration of fluticasone and LEXIVA/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.
Narcotic analgesic: Methadone ↓Methadone Data suggest that the interaction is not clinically relevant; however, patients should be monitored for opiate withdrawal symptoms.
Oral contraceptives: Ethinyl estradiol/norethindronea LEXIVA: ↓Amprenavir ↓Ethinyl estradiol LEXIVA/ritonavir: ↓Ethinyl estradiol Alternative methods of non-hormonal contraception are recommended. May lead to loss of virologic response.a Increased risk of transaminase elevations. No data are available on the use of LEXIVA/ritonavir with other hormonal therapies, such as hormone replacement therapy (HRT) for postmenopausal women.
PDE5 inhibitors: Sildenafil, tadalafil, vardenafil ↑Sildenafil ↑Tadalafil ↑Vardenafil May result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH):
Proton pump inhibitors: Esomeprazolea, lansoprazole, omeprazole, pantoprazole, rabeprazole LEXIVA: ↔Amprenavir ↑Esomeprazole LEXIVA/ritonavir: ↔Amprenavir ↔Esomeprazole Proton pump inhibitors can be administered at the same time as a dose of LEXIVA with no change in plasma amprenavir concentrations.
Tricyclic antidepressants: Amitriptyline, imipramine ↑Tricyclics Therapeutic concentration monitoring is recommended for tricyclic antidepressants.


Table name:
Bleeding times
Clinical Impact:
Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention:
This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact:
The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention:
Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact:
Naproxen  may interfere with some urinary assays of 5-hydroxy  indoleacetic acid (5HIAA).
Intervention:
This  effect should be  kept in mind when  urinary  5-hydroxy  indoleacetic acid is determined.


Table name:
Bleeding times
Clinical Impact: Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention: This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact: The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention: Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact: Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention: This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.


Table name:
DRUG DESCRIPTION OF INTERACTION
Sulfonylureas Hypoglycemia potentiated.
Methotrexate Decreases tubular reabsorption; clinical toxicity from methotrexate can result.
Oral Anticoagulants Increased bleeding.


Table name:
Table 4 Other Potentially Significant Drug Interactions
Concomitant Drug Class or Food Noted or Anticipated Outcome Clinical Comment
HMG-Co A Reductase Inhibitors:
atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin
Pharmacokinetic and/or pharmacodynamic interaction: the addition of one drug to a stable long-term regimen of the other has resulted in myopathy and rhabdomyolysis (including a fatality) P-gp substrate; rhabdomyolysis has been reported Weigh the potential benefits and risks and carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during initial therapy; monitoring CPK (creatine phosphokinase) will not necessarily prevent the occurrence of severe myopathy.
Other Lipid-Lowering Drugs:
fibrates, gemfibrozil
Digitalis Glycosides:
digoxin


Table name:
Table 3 Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table 4 for Magnitude of Interaction.
* The interaction between nevirapine and the drug was evaluated in a clinical study. All other drug interactions shown are predicted.
Drug Name Effect on Concentration of Nevirapine or Concomitant Drug Clinical Comment
HIV Antiviral Agents: Protease Inhibitors (PIs)
Atazanavir/Ritonavir* ↓ Atazanavir

↑ Nevirapine
Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures.
Fosamprenavir*



Fosamprenavir/Ritonavir*
↓Amprenavir
↑Nevirapine

↓Amprenavir
↑Nevirapine
Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.

No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied.
Indinavir* ↓ Indinavir The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established.
Lopinavir/Ritonavir* ↓ Lopinavir Dosing in adult patients:

A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.

Dosing in pediatric patients:

Please refer to the Kaletra® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.
Nelfinavir* ↓Nelfinavir M8 Metabolite
↓Nelfinavir Cmin
The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established.
Saquinavir/ritonavir The interaction between nevirapine and saquinavir/ritonavir has not been evaluated The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz*


Delavirdine
Etravirine
Rilpivirine
↓Efavirenz The appropriate doses of these combinations with respect to safety and efficacy have not been established.

Plasma concentrations may be altered.
Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial.
Other Agents
Analgesics:
Methadone*
↓Methadone Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Antiarrhythmics:
Amiodarone, disopyramide, lidocaine
Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Antibiotics:
Clarithromycin*








Rifabutin*







Rifampin*
↓Clarithromycin
↑14-OH clarithromycin








↑Rifabutin







↓ Nevirapine
Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium aviumintracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.

Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.

Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Anticonvulsants:
Carbamazepine, clonazepam, ethosuximide
Plasma concentrations of nevirapine and the anticonvulsant may be decreased. Use with caution and monitor virologic response and levels of anticonvulsants.
Antifungals:
Fluconazole*





Ketoconazole*




Itraconazole
↑Nevirapine






↓ Ketoconazole




↓ Itraconazole
Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events.


Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.

Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug.
Antithrombotics:
Warfarin
Plasma concentrations may be increased. Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.
Calcium channel blockers:
Diltiazem, nifedipine, verapamil
Plasma concentrations may be decreased. Appropriate doses for these combinations have not been established.
Cancer chemotherapy:
Cyclophosphamide
Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Ergot alkaloids:
Ergotamine
Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Immunosuppressants: Cyclosporine, tacrolimus, sirolimus Plasma concentrations may be decreased. Appropriate doses for these combinations have not been established.
Motility agents:
Cisapride
Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Opiate agonists:
Fentanyl
Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Oral contraceptives:
Ethinyl estradiol and Norethindrone*
↓ Ethinyl estradiol
↓ Norethindrone
Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended.


Table name:
Inhibitors of CYP3A4 and CYP2D6
Clinical Impact: The concomitant use of oxycodone hydrochloride tablets and CYP3A4 inhibitors can increase the plasma concentration of oxycodone, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of oxycodone hydrochloride tablets and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of oxycodone hydrochloride tablets is achieved [see Warnings and Precautions (5.4)]. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the oxycodone plasma concentration will decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to oxycodone.
Intervention: If concomitant use is necessary, consider dosage reduction of oxycodone hydrochloride tablets until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the oxycodone hydrochloride tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir).
CYP3A4 Inducers
Clinical Impact: The concomitant use of oxycodone hydrochloride tablets and CYP3A4 inducers can decrease the plasma concentration of oxycodone [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to oxycodone [see Warnings and Precautions (5.12)]. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the oxycodone plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.
Intervention: If concomitant use is necessary, consider increasing the oxycodone hydrochloride tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider oxycodone hydrochloride tablets dosage reduction and monitor for signs of respiratory depression.
Examples: Rifampin, carbamazepine, phenytoin
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.5)].
Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Adverse Reactions (6.2)].
Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue oxycodone hydrochloride tablets if serotonin syndrome is suspected.
Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)].
Intervention: The use of oxycodone hydrochloride tablets is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
Examples: phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist Opioid Analgesics
Clinical Impact: May reduce the analgesic effect of oxycodone hydrochloride tablets and/or may precipitate withdrawal symptoms.
Intervention: Avoid concomitant use
Examples: Butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact: Oxycodone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of oxycodone hydrochloride tablets and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention: Monitor patients for signs of dismissed diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact: The concomitant risk of anticholinergic drugs may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when oxycodone hydrochloride tablets are used concurrently with anticholinergic drugs.


Table name:
Table 3Drugs that Can Increase the Risk of Bleeding
Drug  Class
Specific  Drugs
Anticoagulants 
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin 
Antiplatelet Agents 
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine 
Nonsteroidal Anti-Inflammatory Agents 
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac 
Serotonin Reuptake Inhibitors 
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone 


Table name:
Interacting Drug
Interaction
Theophylline
Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin
Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents
Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin
Monitor phenytoin level (7)
Methotrexate
Monitor for methotrexate toxicity (7)
Cyclosporine
May increase serum creatinine. Monitor serum creatinine (7)
Multivalent cation-containing products including antacids, metal cations or didanosine
Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin (7)


Table name:
Drugs That Interfere with Hemostasis
Clinical Impact: • Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of naproxen or naproxen sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: Concomitant use of naproxen or naproxen sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen or naproxen sodium is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE-inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: • During concomitant use of naproxen or naproxen sodium and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of naproxen or naproxen sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen or naproxen sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact: The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of naproxen or naproxen sodium and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen or naproxen sodium and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of naproxen or naproxen sodium and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of naproxen or naproxen sodium and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of naproxen or naproxen sodium and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of naproxen or naproxen sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of naproxen or naproxen sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact: Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention: Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen or naproxen sodium is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed release tablets are not recommended.
Cholestyramine
Clinical Impact: Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention: Concomitant administration of cholestyramine with naproxen or naproxen sodium is not recommended.
Probenecid
Clinical Impact: Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention: Patients simultaneously receiving naproxen or naproxen sodium and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact: Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention: Patients simultaneously receiving naproxen or naproxen sodium and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.


Table name:
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat containing products), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice Avoid grapefruit juice


Table name:
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin dailyFor patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice Avoid grapefruit juice


Table name:
Interacting DrugInteracting Drug InteractionInteraction
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products.
Warfarin
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( 7.2)
Antidiabetic agents
Carefully monitor blood glucose ( 5.11, 7.3)


Table name:
AED Co-administered AED Concentration Topiramate Concentration
Phenytoin NC or 25% increasea 48% decrease
Carbamazepine (CBZ) NC 40% decrease
CBZ epoxideb NC NE
Valproic acid 11% decrease 14% decrease
Phenobarbital NC NE
Primidone NC NE
Lamotrigine NC at TPM doses up to 400 mg/day 13% decrease


Table name:
Table 2 Steady-State Plasma Concentrations of Felbatol When Coadministered With Other AEDs
*Not administered but an active metabolite of carbamazepine.
**No significant effect.
AED
Coadministered
AED
Concentration
Felbatol®
Concentration
Phenytoin
Valproate ↔**
Carbamazepine (CBZ)
*CBZ epoxide

Phenobarbital


Table name:
Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Interacting Agent Examples
Drugs whose efficacy is impaired by phenytoin
Azoles Fluconazole, ketoconazole, itraconazole, posaconazole, voriconazole
Antineoplastic agents Irinotecan, paclitaxel, teniposide
Delavirdine Phenytoin can substantially reduce the concentrations of delavirdine. This can lead to loss of virologic response and possible resistance [see Contraindications (4)].
Neuromuscular blocking agents Cisatracurium, pancuronium, rocuronium and vecuronium: resistance to the neuromuscular blocking action of the nondepolarizing neuromuscular blocking agents has occurred in patients chronically administered phenytoin. Whether or not phenytoin has the same effect on other non-depolarizing agents is unknown. Prevention or Management: Patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected, and infusion rate requirements may be higher.
Warfarin Increased and decreased PT/INR responses have been reported when phenytoin is co-administered with warfarin
Other Corticosteroids, doxycycline, estrogens, furosemide, oral contraceptives, paroxetine, quinidine, rifampin, sertraline, theophylline, and vitamin D
Drugs whose level is decreased by phenytoin
Antiepileptic drugsa Carbamazepine, felbamate, lamotrigine, topiramate, oxcarbazepine
Antilipidemic agents Atorvastatin, fluvastatin, simvastatin
Antiviral agents Efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir Fosamprenavir: phenytoin when given with fosamprenavir alone may decrease the concentration of amprenavir, the active metabolite. Phenytoin when given with the combination of fosamprenavir and ritonavir may increase the concentration of amprenavir.
Calcium channel blockers Nifedipine, nimodipine, nisoldipine, verapamil
Other Albendazole (decreases active metabolite), chlorpropamide, clozapine, cyclosporine, digoxin, folic acid, methadone, mexiletine, praziquantel, quetiapine


Table name:
Interacting Agents Prescribing Recommendations
Itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Amiodarone, verapamil, diltiazem Do not exceed 10 mg simvastatin daily
Amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Grapefruit juice Avoid large quantities of grapefruit juice (> 1 quart daily)


Table name:
 Interacting Drug  Interaction
 Valproic acid  Doripenem reduced the serum concentrations of valproic acid to below the therapeutic concentration range in healthy subjects (7.1)
 Probenecid  Reduces renal clearance of doripenem, resulting in increased doripenem concentrations (7.2, 12.3)
 Drugs metabolized by cytochrome P450 enzymes  Doripenem neither inhibits nor induces major cytochrome P450 enzymes (12.3)


Table name:
Table 4 Drugs Tested in In Vitro Binding or In Vivo Drug Interaction Testing or With Post-Marketing Reports
a Should be administered at least 4 hours prior to WELCHOL
b No significant alteration of warfarin drug levels with warfarin and WELCHOL coadministration in an in vivo study which did not evaluate warfarin pharmacodynamics (INR). [See Post-marketing Experience (6.2)]
c Cyclosporine levels should be monitored and, based on theoretical grounds, cyclosporine should be administered at least 4 hours prior to WELCHOL.
Drugs with a known interaction with colesevelam Cyclosporinec, glyburidea, levothyroxinea, and oral contraceptives containing ethinyl estradiol and norethindronea
Drugs with postmarketing reports consistent with potential drug-drug interactions when coadministered with WELCHOL phenytoina, warfarinb
Drugs that do not interact with colesevelam based on in vitro or in vivo testing cephalexin, ciprofloxacin, digoxin, warfarinb fenofibrate, lovastatin, metformin, metoprolol, pioglitazone, quinidine, repaglinide, valproic acid, verapamil


Table name:
Interacting Agents
Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol

Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone
Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine
Do not exceed 20 mg simvastatin daily
Lomitapide 
For patients with HoFH, do not exceed 20 mg simvastatin daily* 
Grapefruit juice
Avoid grapefruit juice


Table name:
Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.*
* Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol,lomefloxacin
   systemic and inhaledmebendazole
amoxicillinmedroxyprogesterone
ampicillin,methylprednisolone
   with or without sulbactammetronidazole
atenololmetoprolol
azithromycinnadolol
Caffeine,nifedipine
   dietary ingestionnizatidine
cefactornorfloxacin
co-trimoxazoleofloxacin
   (trimethoprim andomeprazole
   sulfamethoxazole)prednisone, prednisolone
diltiazemranitidine
dirithromycinrifabutin
enfluraneroxithromycin
famotidinesorbitol
felodipine   (purgative doses do not
finasteride   inhibit theophylline
hydrocortisone   absorption)
isofluranesucralfate
isoniazid terbutaline,systemic
isradipineterfenadine
influenza vaccinetetracycline
ketoconazoletocainide


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor
(boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
CYP2C19 or CYP3A4 Inducers
Clinical Impact: Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology (12.3)].
Intervention: St. John’s Wort, rifampin: Avoid concomitant use with omeprazole [see Warnings and Precautions (5.9)].

Ritonavir-containing products: see prescribing information for specific drugs.
CYP2C19 or CYP3A4 Inhibitors
Clinical Impact: Increased exposure of omeprazole [see Clinical Pharmacology (12.3)].
  Intervention: Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered.

See prescribing information for voriconazole.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
* For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Interacting Agents
Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol
Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone
Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine
Do not exceed 20 mg simvastatin daily
Lomitapide
For patients with HoFH, do not exceed 20 mg simvastatin daily*
Grapefruit juice
Avoid grapefruit juice


Table name:
Interacting Drug Interaction
Theophylline Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin Monitor phenytoin level (7)
Methotrexate Monitor for methotrexate toxicity (7)
Cyclosporine May increase serum creatinine. Monitor serum creatinine (7)


Table name:
Table 7 Summary of AED Interactions with Oxcarbazepine Tablets, USP
AED Coadministered Dose of AED
(mg/day)
Oxcarbazepine Tablets Dose
(mg/day)
Influence of Oxcarbazepine Tablets on AED Concentration
(Mean Change, 90% Confidence Interval)
Influence of AED on MHD Concentration
(Mean Change, 90% Confidence Interval)
Carbamazepine 400-2000 900 ncnc denotes a mean change of less than 10% 40% decrease
[CI: 17% decrease, 57% decrease]
Phenobarbital 100-150 600-1800 14% increase
[CI: 2% increase, 24% increase]
25% decrease
[CI: 12% decrease, 51% decrease]
Phenytoin 250-500 600-1800
>1200-2400
nc , Pediatrics up to 40% increaseMean increase in adults at high oxcarbazepine tablets, USP doses
[CI: 12% increase, 60% increase]
30% decrease
[CI: 3% decrease, 48% decrease]
Valproic acid 400-2800 600-1800 nc 18% decrease
[CI: 13% decrease, 40% decrease]


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 7.8, 12.3)
Interacting Agents Prescribing Recommendations
Strong CYP3A4 Inhibitors, (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin,
clarithromycin, telithromycin,
HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol
Contraindicated with VYTORIN
Verapamil, diltiazem, dronedarone Do not exceed 10/10 mg VYTORIN daily
Amiodarone, amlodipine, ranolazine Do not exceed 10/20 mg VYTORIN daily
Lomitapide For patients with HoFH, do not exceed 10/20 mg VYTORIN dailyFor patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 10/40 mg VYTORIN when taking lomitapide.
Grapefruit juice Avoid grapefruit juice


Table name:
Table 18. Summary of Effect of Co-administered Drugs on Exposure to Active Moiety (Risperidone + 9- Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Co-administered Drug  Dosing Schedule  Effect on Active Moeity (Risperidone + 9-Hydroxy-Risperidone (RatioChange relative to reference Risperidone Dose Recommendation 
  Co-administered Drug  Risperidone  AUC  Cmax   
Enzyme (CYP2D6) Inhibitors           
Fluoxetine  20 mg/day  2 or 3 twice daily  1.4  1.5  Re-evaluate dosing. Do not exceed 8 mg/day 
Paroxetine  10 mg/day  4 mg/day  1.3   - Re-evaluate dosing. Do not exceed 8 mg/day
  20 mg/day  4 mg/day  1.6   -   
  40 mg/day  4 mg/day  1.8   -  
Enzyme (CYP3A/PgP inducers) Inducers          
Carbamazepine 573 ± 168 mg/day  3 mg twice daily  0.51 0.55  Titrate dose upwards. Do not exceed twice the patient’s usual dose 
Enzyme (CYP3A) Inhibitors          
Ranitidine  150 mg twice daily  1 mg single dose  1.2  1.4  Dose adjustment not needed 
Cimetidine  400 mg twice daily  1 mg single dose  1.1  1.3  Dose adjustment not needed 
Erythromycin  500 mg four times daily  1 mg single dose  1.1  0.94  Dose adjustment not needed 
Other Drugs           
Amitriptyline  50 mg twice daily  3 mg twice daily  1.2  1.1  Dose adjustment not needed 


Table name:
Beta-Blockers
Clinical Impact:
The concomitant use of beta-blockers and Glucagon for Injection may increase the risk of a temporary increase in heart rate and blood pressure. 
Intervention:
The increase in blood pressure and heart rate may require therapy in patients with coronary artery disease.
Insulin
Clinical Impact:
Insulin reacts antagonistically towards glucagon. 
Intervention:
Monitor blood glucose when Glucagon for Injection is used as a diagnostic aid in diabetes patients.
Indomethacin
Clinical Impact:
The concomitant use of indomethacin and Glucagon for Injection may lead to hypoglycemia.
Intervention:
Monitor blood glucose levels during glucagon treatment of patients taking indomethacin.
Anticholinergic Drugs
Clinical Impact:
The concomitant use of anticholinergic drugs and Glucagon for Injection increase the risk of gastrointestinal adverse reactions due to additive effects on inhibition of gastrointestinal motility.
Intervention:
Concomitant use is not recommended.
Warfarin
Clinical Impact:
Glucagon may increase the anticoagulant effect of warfarin.
Intervention:
Monitor patients for unusual bruising or bleeding, as adjustments in warfarin dosage may be required.


Table name:
Drug Description of Interaction
Tolbutamide; Sulfonylureas Hypoglycemia potentiated
Methotrexate Decreases tubular reabsorption; clinical toxicity from methotrexate can result
Oral Anticoagulant Increased bleeding


Table name:
Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s) Recommendation Comments
Tizanidine Contraindicated Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)].
Theophylline Avoid Use (Plasma Exposure Likely to be Increased and Prolonged) Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate[see Warnings and Precautions (5.6).]
Drugs Known to Prolong QT Interval Avoid Use Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.10) and Use in Specific Populations (8.5)].
Oral antidiabetic drugs Use with caution Glucose-lowering effect potentiated Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs. [see Adverse Reactions (6.1).]
Phenytoin Use with caution Altered serum levels of phenytoin (increased and decreased) To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after coadministration of ciprofloxacin with phenytoin.
Cyclosporine Use with caution (transient elevations in serum creatinine) Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs Use with caution (Increase in anticoagulant effect) The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole Use with caution Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after coadministration with ciprofloxacin [see Warnings and Precautions (5.15)].
Clozapine Use with caution Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs Use with caution Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil Use with caution 2-fold increase in exposure Monitor for sildenafil toxicity (see Pharmacokinetics -(12.3)-].
Duloxetine Avoid Use 5-fold increase in duloxetine exposure If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products) Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2)]. Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels) Potentiation of ciprofloxacin toxicity may occur.


Table name:
Table 3 Clinically Significant Drug Interactions with Meloxicam
Drugs  that  Interfere  with  Hemostasis
Clinical  Impact :
Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.
Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. 
Intervention
Monitor patients with concomitant use of meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see  Warnings  and  Precautions  ( 5 . 11)]. 
Aspirin 
Clinical  Impact
Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see  Warnings  and  Precautions  ( 5 . 2)]. 
Intervention
Concomitant use of meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see  Warnings  and  Precautions  ( 5 . 11)]. 

Meloxicam is not a substitute for low dose aspirin for cardiovascular protection. 
ACE  Inhibitors Angiotensin  Receptor  Blockers or  Beta - Blockers 
Clinical  Impact

NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). 
In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. 
Intervention

During concomitant use of meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. 
During concomitant use of meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see  Warnings  and  Precautions  ( 5 . 6)]. 
When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. 
Diuretics 

Clinical  Impact

Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. 
Intervention

During concomitant use of meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see  Warnings  and  Precautions  ( 5 . 6)]. 
Lithium 
Clinical  Impact

NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [see  Clinical  Pharmacology  ( 12 . 3)]. 
Intervention

During concomitant use of meloxicam and lithium, monitor patients for signs of lithium toxicity. 
Methotrexate 
Clinical  Impact

Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention

During concomitant use of meloxicam and methotrexate, monitor patients for methotrexate toxicity. 
Cyclosporine 

Clinical  Impact

Concomitant use of meloxicam and cyclosporine may increase cyclosporine’s nephrotoxicity. 
Intervention

During concomitant use of meloxicam and cyclosporine, monitor patients for signs of worsening renal function. 
NSAIDs  and  Salicylates 

Clinical  Impact

Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see  Warnings  and  Precautions  ( 5 . 2)]. 
Intervention

The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended. 
Pemetrexed 

Clinical  Impact

Concomitant use of meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). 
Intervention

During concomitant use of meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended. 


Table name:
Interacting Drug Interaction
   Multivalent cation-containing products
   including antacids, metal cations or didanosine
   Absorption of levofloxacin is decreased when the tablet
   formulation  is taken within 2 hours of this product. (2.4, 7.1)
   Warfarin
   Effect may be enhanced. Monitor prothrombin time,
   INR, watch for bleeding (7.2)
   Antidiabetic agents
   Carefully monitor blood glucose (5.12, 7.3)


Table name:
Interacting  Drug  Interaction
Multivalent cation-containing
products including antacids,
metal cations or didanosine
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidibetic agents Carefully monitor blood glucose (5.11, 7.3)


Table name:
Table 5. Clinically-Significant Drug Interactions with Sertraline Hydrochloride
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:
The concomitant use of SSRIs including sertraline hydrochloride and MAOIs increases the risk of serotonin syndrome.
Intervention:
Sertraline hydrochloride is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [See Dosage and Administration (2.5), Contraindications (4), Warnings and Precautions (5.2)].
Examples:
selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue
Pimozide
Clinical Impact:
Increased plasma concentrations of pimozide, a drug with a narrow therapeutic index, may increase the risk of QT prolongation and ventricular arrhythmias.
Intervention:
Concomitant use of pimozide and sertraline hydrochloride is contraindicated [See Contraindications (4)].
Other Serotonergic Drugs
Clinical Impact:
The concomitant use of serotonergic drugs with sertraline hydrochloride increases the risk of serotonin syndrome.
Intervention:
Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of sertraline hydrochloride and/or concomitant serotonergic drugs [See Warnings and Precautions (5.2)].
Examples:
other SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort
Drugs that Interfere with Hemostasis (antiplatelet agents and anticoagulants)
Clinical Impact:
The concurrent use of an antiplatelet agent or anticoagulant with sertraline hydrochloride may potentiate the risk of bleeding.
Intervention:
Inform patients of the increased risk of bleeding associated with the concomitant use of sertraline hydrochloride and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio [See Warnings and Precautions (5.3)].
Examples:
aspirin, clopidogrel, heparin, warfarin
Drugs Highly Bound to Plasma Protein
Clinical Impact:
Sertraline hydrochloride is highly bound to plasma protein. The concomitant use of sertraline hydrochloride with another drug that is highly bound to plasma protein may increase free concentrations of sertraline hydrochloride or other tightly-bound drugs in plasma [See Clinical Pharmacology (12.3)] .
Intervention:
Monitor for adverse reactions and reduce dosage of sertraline hydrochloride or other protein-bound drugs as warranted.
Examples:
warfarin
Drugs Metabolized by CYP2D6
Clinical Impact:
Sertraline hydrochloride is a CYP2D6 inhibitor [See Clinical Pharmacology (12.3)] . The concomitant use of sertraline hydrochloride with a CYP2D6 substrate may increase the exposure of the CYP2D6 substrate.
Intervention:
Decrease the dosage of a CYP2D6 substrate if needed with concomitant sertraline hydrochloride use. Conversely, an increase in dosage of a CYP2D6 substrate may be needed if sertraline hydrochloride is discontinued.
Examples:
propafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, thoridazine, tolterodine, venlafaxine
Phenytoin
Clinical Impact:
Phenytoin is a narrow therapeutic index drug. Sertraline hydrochloride may increase phenytoin concentrations.
Intervention:
Monitor phenytoin levels when initiating or titrating sertraline hydrochloride. Reduce phenytoin dosage if needed.
Examples:
phenytoin, fosphenytoin


Table name:
Table 4 Drugs Having Clinically Important Interactions with Amphetamines
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact Concomitant use of MAOIs and CNS stimulants can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure.
Intervention Do not administer dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate and amphetamine sulfate extended-release capsules concomitantly or within 14 days after discontinuing MAOI [see CONTRAINDICATIONS (4) and WARNINGS AND PRECAUTIONS (5.6)].
Examples selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue
Serotonergic Drugs
Clinical Impact The concomitant use of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate and amphetamine sulfate extended-release capsules and serotonergic drugs increases the risk of serotonin syndrome.
Intervention Initiate with lower doses and monitor patients for signs and symptoms of serotonin syndrome, particularly during dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate and amphetamine sulfate extended-release capsules initiation or dosage increase. If serotonin syndrome occurs, discontinue dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate and amphetamine sulfate extended-release capsules and the concomitant serotonergic drug(s) [see WARNINGS AND PRECAUTIONS (5.6)].
Examples selective serotonin reuptake inhibitors (SSRI), serotonin norepinephrine reuptake inhibitors (SNRI), triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort
CYP2D6 Inhibitors
Clinical Impact The concomitant use of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate and amphetamine sulfate extended-release capsules and CYP2D6 inhibitors may increase the exposure of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate and amphetamine sulfate extended-release capsules compared to the use of the drug alone and increase the risk of serotonin syndrome.
Intervention Initiate with lower doses and monitor patients for signs and symptoms of serotonin syndrome particularly during dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate and amphetamine sulfate extended-release capsules initiation and after a dosage increase. If serotonin syndrome occurs, discontinue dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate and amphetamine sulfate extended-release capsules and the CYP2D6 inhibitor [see WARNINGS AND PRECAUTIONS (5.6) and OVERDOSAGE (10)].
Examples paroxetine and fluoxetine (also serotonergic drugs), quinidine, ritonavir
Alkalinizing Agents
Clinical Impact Increase blood levels and potentiate the action of amphetamine.
Intervention Co-administration of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate and amphetamine sulfate extended-release capsules and gastrointestinal or urinary alkalinizing agents should be avoided.
Examples Gastrointestinal alkalinizing agents (e.g., sodium bicarbonate). Urinary alkalinizing agents (e.g. acetazolamide, some thiazides).
Acidifying Agents
Clinical Impact Lower blood levels and efficacy of amphetamines.
Intervention Increase dose based on clinical response.
Examples Gastrointestinal acidifying agents (e.g., guanethidine, reserpine, glutamic acid HCl, ascorbic acid). Urinary acidifying agents (e.g., ammonium chloride, sodium acid phosphate, methenamine salts).
Tricyclic Antidepressants
Clinical Impact May enhance the activity of tricyclic or sympathomimetic agents causing striking and sustained increases in the concentration of d-amphetamine in the brain; cardiovascular effects can be potentiated.
Intervention Monitor frequently and adjust or use alternative therapy based on clinical response.
Examples desipramine, protriptyline
Proton Pump Inhibitors
Clinical Impact Time to maximum concentration (Tmax) of amphetamine is decreased compared to when administered alone.
Intervention Monitor patients for changes in clinical effect and adjust therapy based on clinical response.
Examples omeprazole


Table name:
Interacting Drug Interaction
   Multivalent cation-containing products
   including antacids, metal cations or didanosine
   Absorption of levofloxacin is decreased when the tablet
   formulation  is taken within 2 hours of this product. (2.4, 7.1)
   Warfarin
   Effect may be enhanced. Monitor prothrombin time,
   INR, watch for bleeding (7.2)
   Antidiabetic agents
   Carefully monitor blood glucose (5.11, 7.3)


Table name:
AED Co-administered AED Concentration Topiramate Concentration
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated
Phenytoin NC or 25% increase = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. 48% decrease
Carbamazepine (CBZ) NC 40% decrease
CBZ epoxide = Is not administered but is an active metabolite of carbamazepine. NC NE
Valproic acid 11% decrease 14% decrease
Phenobarbital NC NE
Primidone NC NE
Lamotrigine NC at TPM doses up to 400 mg/day 13% decrease


Table name:
Table 5 Effects on steady-state fexofenadine pharmacokinetics after 7 days of co-administration with fexofenadine hydrochloride 120 mg every 12 hours in healthy adult subjects (n=24)
Concomitant Drug CmaxSS
(Peak plasma concentration)
AUCss(0-12h)
(Extent of systemic exposure)
Erythromycin
(500 mg every 8 hrs)
+82% +109%
Ketoconazole
(400 mg once daily)
+135% +164%


Table name:
Drug Interactions Associated with Increased Risk of  Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice Avoid grapefruit juice


Table name:
Table II. Clinically significant drug interactions with theophylline.Refer to PRECAUTIONS, Drug Interactions for further information regarding table.
Drug Type of Interaction EffectAverage effect on steady-state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.
Adenosine Theophylline blocks adenosine receptors. Higher doses of adenosine may be required to achieve desired effect.
Alcohol A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours. 30% increase
Allopurinol Decreases theophylline clearance at allopurinol doses ≥600 mg/day. 25% increase
Aminoglutethimide Increases theophylline clearance by induction of microsomal enzyme activity. 25% decrease
Carbamazepine Similar to aminoglutethimide. 30% decrease
Cimetidine Decreases theophylline clearance by inhibiting cytochrome P450 1A2. 70% increase
Ciprofloxacin Similar to cimetidine. 40% increase
Clarithromycin Similar to erythromycin. 25% increase
Diazepam Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram Decreases theophylline clearance by inhibiting hydroxylation and demethylation. 50% increase
Enoxacin Similar to cimetidine. 300% increase
Ephedrine Synergistic CNS effects Increased frequency of nausea, nervousness, and insomnia.
Erythromycin Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3. 35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown. 30% increase
Flurazepam Similar to diazepam. Similar to diazepam.
Fluvoxamine Similar to cimetidine. Similar to cimetidine.
Halothane Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines. Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-A Decreases theophylline clearance. 100% increase
Isoproterenol (IV) Increase theophylline clearance. 20% increase
Ketamine Pharmacologic May lower theophylline seizure threshold.
Lithium Theophylline increases renal lithium clearance. Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam Similar to diazepam. Similar to diazepam.
Methotrexate (MTX) Decreases theophylline clearance. 20% increase after low dose MTX, higher dose MTX may have a greater effect.
Mexiletine Similar to disulfiram. 80% increase
Midazolam Similar to diazepam. Similar to diazepam.
Moricizine Increases theophylline clearance. 25% decrease
Pancuronium Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition. Larger dose of pancuronium may be required to achieve neuromuscular blockade.
Pentoxifylline Decreases theophylline clearance. 30% increase
Phenobarbital (PB) Similar to aminoglutethimide. 25% decrease after two weeks of concurrent PB.
Phenytoin Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption. Serum theophylline and phenytoin concentrations decrease about 40%.
Propafenone Decreases theophylline clearance and pharmacologic interaction. 40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Propranolol Similar to cimetidine and pharmacologic interaction. 100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Rifampin Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity. 20 to 40% decrease
Sulfinpyrazone Increase theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline. 20% increase
Tacrine Similar to cimetidine, also increases renal clearance of theophylline. 90% increase
Thiabendazole Decreases theophylline clearance. 190% increase
Ticlopidine Decreases theophylline clearance. 60% increase
Troleandomycin Similar to erythromycin. 33 to 100% increase depending on troleandomycin dose.
Verapamil Similar to disulfiram. 20% increase


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide

Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide






Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T and T levels and increase TSH, although all values remain within normal limits in most patients. 4 3
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate










Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
  Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration   Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen





Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid


Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)





Administration of these agents with levothyroxine results in an initial transient increase in FT . Continued administration results in a decrease in serum T and normal FT and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T and T to TBG and transthyretin. An initial increase in serum FT , is followed by return of FT to normal levels with sustained therapeutic serum salicylate concentrations, although total-T levels may decrease by as much as 30%. 4 4 4 4 3 4 4 4
  Drugs that may alter T 4 and T 3 metabolism
  Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin


Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. 4
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)




Administration of these enzyme inhibitors decrease the peripheral conversion of T to T , leading to decreased T levels. However, serum T levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T and T levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T concentrations by 30% with minimal change in serum T levels. However, long-term glucocorticoid therapy may result in slightly decreased T and T levels due to decreased TBG production (see above). 4 3 3 4 3 4 3 4 3 4
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives

Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)


Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin




Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2

Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin

Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of I, I, and Tc. 123 131 99m
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics









These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 2: Drug Interactions: Pharmacokinetic Parameters for Indinavir in the Presence of the Coadministered Drug (See PRECAUTIONS, Table 9 for Recommended Alterations in Dose or Regimen)
Coadministered drug Dose of Coadministered drug (mg) Dose of CRIXIVAN
(mg)
n Ratio (with/without coadministered drug) of Indinavir
Pharmacokinetic Parameters
(90% CI); No Effect = 1.00
Cmax AUC Cmin
All interaction studies conducted in healthy, HIV-negative adult subjects, unless otherwise indicated.
Cimetidine 600 twice daily,
6 days
400 single dose 12 1.07
(0.77, 1.49)
0.98
(0.81, 1.19)
0.82
(0.69, 0.99)
Clarithromycin 500 q12h,
7 days
800 three times
daily, 7 days
10 1.08
(0.85, 1.38)
1.19
(1.00, 1.42)
1.57
(1.16, 2.12)
Delavirdine 400 three times daily 400 three times
daily, 7 days
28 0.64Relative to indinavir 800 mg three times daily alone.
(0.48, 0.86)
No significant change 2.18
(1.16, 4.12)
Delavirdine 400 three times daily 600 three times
daily, 7 days
28 No significant change 1.53
(1.07, 2.20)
3.98
(2.04, 7.78)
EfavirenzStudy conducted in HIV-positive subjects. 600 once daily,
10 days
1000 three times
daily, 10 days
20
After morning dose No significant change 0.67
(0.61, 0.74)
0.61
(0.49, 0.76)
After afternoon dose No significant change 0.63
(0.54, 0.74)
0.48
(0.43, 0.53)
After evening dose 0.71
(0.57, 0.89)
0.54
(0.46, 0.63)
0.43
(0.37, 0.50)
Fluconazole 400 once daily,
8 days
1000 three times daily, 7 days 11 0.87
(0.72, 1.05)
0.76
(0.59, 0.98)
0.90
(0.72, 1.12)
Grapefruit Juice 8 oz. 400 single dose 10 0.65
(0.53, 0.79)
0.73
(0.60, 0.87)
0.90
(0.71, 1.15)
Isoniazid 300 once daily in the morning,
8 days
800 three times daily, 7 days 11 0.95
(0.88, 1.03)
0.99
(0.87, 1.13)
0.89
(0.75, 1.06)
Itraconazole 200 twice daily,
7 days
600 three times
daily, 7 days
12 0.78
(0.69, 0.88)
0.99
(0.91, 1.06)
1.49
(1.28, 1.74)
Ketoconazole 400 once daily,
7 days
600 three times
daily, 7 days
12 0.69
(0.61, 0.78)
0.80
(0.74, 0.87)
1.29
(1.11, 1.51)
400 once daily,
7 days
400 three times
daily, 7 days
12 0.42
(0.37, 0.47)
0.44
(0.41, 0.48)
0.73
(0.62, 0.85)
Methadone 20-60 once daily in the morning,
8 days
800 three times
daily, 8 days
10 See text below for discussion of interaction.
Quinidine 200 single dose 400 single dose 10 0.96
(0.79, 1.18)
1.07
(0.89, 1.28)
0.93
(0.73, 1.19)
Rifabutin 150 once daily in the morning,
10 days
800 three times
daily, 10 days
14 0.80
(0.72, 0.89)
0.68
(0.60, 0.76)
0.60
(0.51, 0.72)
Rifabutin 300 once daily in the morning,
10 days
800 three times
daily, 10 days
10 0.75
(0.61, 0.91)
0.66
(0.56, 0.77)
0.61
(0.50, 0.75)
Rifampin 600 once daily in the morning,
8 days
800 three times
daily, 7 days
12 0.13
(0.08, 0.22)
0.08
(0.06, 0.11)
Not Done
Ritonavir 100 twice daily,
14 days
800 twice
daily, 14 days
10, 16Comparison to historical data on 16 subjects receiving indinavir alone. See text below for discussion of interaction.
Ritonavir 200 twice daily,
14 days
800 twice
daily,14 days
9, 16 See text below for discussion of interaction.
Sildenafil 25 single dose 800 three times daily 6 See text below for discussion of interaction.
St. John's wort
(Hypericum perforatum,
standardized to 0.3 % hypericin)
300 three times daily with meals,
14 days
800 three times daily 8 Not Available 0.46
(0.34, 0.58)95% CI.
0.19
(0.06, 0.33)
Stavudine (d4T) 40 twice daily,
7 days
800 three times
daily, 7 days
11 0.95
(0.80, 1.11)
0.95
(0.80, 1.12)
1.13
(0.83, 1.53)
Trimethoprim/
Sulfamethoxazole
800 Trimethoprim/
160 Sulfamethoxazole q12h, 7 days
400 four times
daily, 7 days
12 1.12
(0.87, 1.46)
0.98
(0.81, 1.18)
0.83
(0.72, 0.95)
Zidovudine 200 three times daily, 7 days 1000 three times
daily, 7 days
12 1.06
(0.91, 1.25)
1.05
(0.86, 1.28)
1.02
(0.77, 1.35)
Zidovudine/
Lamivudine
(3TC)
200/150 three times daily, 7 days 800 three times
daily, 7 days
6, 9Parallel group design; n for indinavir + coadministered drug, n for indinavir alone. 1.05
(0.83, 1.33)
1.04
(0.67, 1.61)
0.98
(0.56, 1.73)


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7.1, 7.2, 7.3, 7.4)
Interacting Agents Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone Avoid simvastatin
Gemfibrozil, cyclosporine, danazol Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil Do not exceed 20 mg simvastatin daily
Diltiazem Do not exceed 40 mg simvastatin daily
Grapefruit juice Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Table 4 Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table 5 for Magnitude of Interaction.
* The interaction between immediate-release nevirapine and the drug was evaluated in a clinical study. The results of drug interaction studies with immediate-release nevirapine are expected to also apply to nevirapine extended-release tablets.
Drug Name
Effect on Concentration of Nevirapine or Concomitant Drug
Clinical Comment
HIV Antiviral Agents: Protease Inhibitors (PIs)
Atazanavir/Ritonavir*
↓ Atazanavir
↑ Nevirapine
Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures.
Fosamprenavir*
 
 
 
Fosamprenavir/Ritonavir*
↓ Amprenavir
↑ Nevirapine
 
 
↓ Amprenavir
↑ Nevirapine
 
Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.
 
No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied.
 
Indinavir*
↓ Indinavir
The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established.
Lopinavir/Ritonavir*
↓Lopinavir
Dosing in adult patients:
 
A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.
 
Dosing in pediatric patients:
 
Please refer to the Kaletra® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.
 
Nelfinavir*
↓ Nelfinavir M8 Metabolite 
↓ Nelfinavir Cmin
The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established.
Saquinavir/ritonavir
The interaction between nevirapine and saquinavir/ritonavir has not been evaluated
The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz*
↓ Efavirenz
The appropriate doses of these combinations with respect to safety and efficacy have not been established.
Delavirdine
Etravirine
Rilpivirine
 
Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial.
Hepatitis C Antiviral Agents
Boceprevir
Plasma concentrations of boceprevir may be decreased due to induction of CYP3A4/5 by nevirapine.
Nevirapine and boceprevir should not be coadministered because decreases in boceprevir plasma concentrations may result in a reduction in efficacy.
Telaprevir
Plasma concentrations of telaprevir may be decreased due to induction of CYP3A4 by nevirapine and plasma concentrations of nevirapine may be increased due to inhibition of CYP3A4 by telaprevir.
Nevirapine and telaprevir should not be coadministered because changes in plasma concentrations of nevirapine, telaprevir, or both may result in a reduction in telaprevir efficacy or an increase in nevirapine-associated adverse events.
Other Agents
Analgesics:
Methadone*
↓ Methadone
Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Antiarrhythmics:
Amiodarone, disopyramide, lidocaine
Plasma concentrations may be decreased.
Appropriate doses for this combination have not been established.
Antibiotics:
Clarithromycin*
↓ Clarithromycin
↑ 14-OH clarithromycin
Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.
Rifabutin*
↑ Rifabutin
Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.
Rifampin*
↓ Nevirapine
Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Anticonvulsants:
Carbamazepine, clonazepam, ethosuximide
Plasma concentrations of nevirapine and the anticonvulsant may be decreased.
Use with caution and monitor virologic response and levels of anticonvulsants.
Antifungals:
Fluconazole*
↑ Nevirapine
Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events.
Ketoconazole*
↓ Ketoconazole
Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.
Itraconazole
↓ Itraconazole
Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug.
Antithrombotics:
Warfarin
Plasma concentrations may be increased.
Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.
Calcium channel blockers:
Diltiazem, nifedipine, verapamil
Plasma concentrations may be decreased.
Appropriate doses for these combinations have not been established.
Cancer chemotherapy:
Cyclophosphamide
Plasma concentrations may be decreased.
Appropriate doses for this combination have not been established.
Ergot alkaloids:
Ergotamine
Plasma concentrations may be decreased.
Appropriate doses for this combination have not been established.
Immunosuppressants:
Cyclosporine, tacrolimus, sirolimus
Plasma concentrations may be decreased.
Appropriate doses for these combinations have not been established.
Motility agents:
Cisapride
Plasma concentrations may be decreased.
Appropriate doses for this combination have not been established.
Opiate agonists:
Fentanyl
Plasma concentrations may be decreased.
Appropriate doses for this combination have not been established.
Oral contraceptives:
Ethinyl estradiol and Norethindrone*
↓ Ethinyl estradiol
↓ Norethindrone
Despite lower ethinyl estradiol and norethindrone exposures when coadministered with nevirapine, literature reports suggest that nevirapine has no effect on pregnancy rates among HIV-infected women on combined oral contraceptives. When coadministered with nevirapine extended-release tablets, no dose adjustment of ethinyl estradiol or norethindrone is needed when used in combination for contraception.

When oral contraceptives are used for hormonal regulation during nevirapine extended-release tablets therapy, the therapeutic effect of the hormonal therapy should be monitored.


Table name:
Table 3: Clinically Relevant Interactions Affecting Drugs Co-Administered with Omeprazole and Interaction with Diagnostics
Antiretrovirals
Clinical Impact:
The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology ( 12.3)]. Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see Clinical Pharmacology (12.3)]. There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole.
Intervention:
Rilpivirine-containing products: Concomitant use with omeprazole is contraindicated [see Contraindications ( 4)] .
 
Atazanavir: Avoid concomitant use with omeprazole. See prescribing information for atazanavir for dosing information.
 
Nelfinavir: Avoid concomitant use with omeprazole. See prescribing information for nelfinavir.
 
Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities.
 
Other antiretrovirals: See prescribing information for specific antiretroviral drugs.
Warfarin
Clinical Impact:
Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
Intervention:
Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range.
Methotrexate
Clinical Impact:
Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions ( 5.11)].
Intervention:
A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate.
CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam)
Clopidogrel
Clinical Impact:
Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology ( 12.3)].
There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel .
Intervention:
Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy [see Warnings and Precautions ( 5.6)].
Citalopram
Clinical Impact:
Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology ( 12.3)] .
Intervention:
Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.
Cilostazol
Clinical Impact:
Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology ( 12.3)].
Intervention:
Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.
Phenytoin
Clinical Impact:
Potential for increased exposure of phenytoin.
Intervention:
Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin.
Diazepam
Clinical Impact:
Increased exposure of diazepam [see Clinical Pharmacology ( 12.3)] .
Intervention:
Monitor patients for increased sedation and reduce the dose of diazepam as needed.
Digoxin
Clinical Impact:
Potential for increased exposure of digoxin [see Clinical Pharmacology ( 12.3)].
Intervention:
Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)
Clinical Impact:
Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
Intervention:
Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF [see Clinical Pharmacology ( 12.3)] .
 
See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact:
Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions.
Intervention:
See Contraindications, Warnings and Precautions  in prescribing information for clarithromycin.
 
See  Drug Interactions in prescribing information for amoxicillin.
Tacrolimus
Clinical Impact:
Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19 .
Intervention:
Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact:
Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions ( 5.10), Clinical Pharmacology ( 12.2)] .
Intervention:
Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
Interaction with Secretin Stimulation Test
Clinical Impact:
Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention:
Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology ( 12.2)] .
False Positive Urine Tests for THC
Clinical Impact:
There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.
Intervention:
An alternative confirmatory method should be considered to verify positive results.
Other
Clinical Impact:
There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram).
Intervention:
Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole.


Table name:
* For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin daily*
Grapefruit juice Avoid grapefruit juice


Table name:
Interacting DrugInteracting Drug InteractionInteraction
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products (2.4, 7.1)
Warfarin
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents
Carefully monitor blood glucose (5.12, 7.3)


Table name:
CYP2C19 or CYP3A4 Inducers
Clinical Impact: Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology ( 12.3)] .
Intervention: St. John’s Wort, rifampin: Avoid concomitant use with omeprazole [see Warnings and Precautions ( 5.9)] .

Ritonavir-containing products: see prescribing information for specific drugs.
CYP2C19 or CYP3A4 Inhibitors
Clinical Impact: Increased exposure of omeprazole [see Clinical Pharmacology ( 12.3)] .
  Intervention: Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered.

See prescribing information for voriconazole.


Table name:
Table 14: Clinically Important Drug Interactions: Effect of other Drugs on Guanfacine Extended-Release Tablets
Concomitant Drug Name or Drug Class Clinical Rationale and Magnitude of Drug Interaction Clinical Recommendation
CYP3A4 inhibitors, e.g.,ketoconazole Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected resulting in a 200% increase in exposure Consider dose reduction [see Dosage and Administration (2.7)]
CYP3A4 inducers, e.g., rifampin Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected resulting in a 60% decrease in exposure Consider dose increase [see Dosage and Administration (2.7)]


Table name:
Table 3 Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table 4 for Magnitude of Interaction.
Drug Name Effect on Concentration of Nevirapine or Concomitant Drug Clinical Comment
HIV Antiviral Agents: Protease Inhibitors (PIs)
Atazanavir/Ritonavir* ↓ Atazanavir
↑ Nevirapine
Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures.
Fosamprenavir*


Fosamprenavir/Ritonavir*
↓ Amprenavir
↑ Nevirapine

↓ Amprenavir
↑ Nevirapine
Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.


No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied.
Indinavir* ↓ Indinavir The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established.
Lopinavir/Ritonavir* ↓Lopinavir Dosing in adult patients:
A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.

Dosing in pediatric patients:
Please refer to the Kaletra® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.
Nelfinavir* ↓Nelfinavir M8 Metabolite
↓Nelfinavir Cmin
The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established.
Saquinavir/ritonavir The interaction between Nevirapine and saquinavir/ritonavir has not been evaluated The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz*



Delavirdine
Etravirine
Rilpivirine
↓ Efavirenz The appropriate doses of these combinations with respect to safety and efficacy have not been established.




Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial.
Other Agents
Analgesics:
Methadone*
↓ Methadone Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Antiarrhythmics: Amiodarone, disopyramide, lidocaine Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Antibiotics:
Clarithromycin* 




Rifabutin*





Rifampin*
↓ Clarithromycin
↑ 14-OH clarithromycin 




↑ Rifabutin





↓ Nevirapine
Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.


Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.




Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Anticonvulsants:
Carbamazepine, clonazepam, ethosuximide
Plasma concentrations of nevirapine and the anticonvulsant may be decreased. Use with caution and monitor virologic response and levels of anticonvulsants.
Antifungals:
Fluconazole*


Ketoconazole*



Itraconazole
↑Nevirapine



↓ Ketoconazole



↓ Itraconazole
Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events.


Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.



Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug.
Antithrombotics:
Warfarin
Plasma concentrations may be increased. Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.
Calcium channel blockers: Diltiazem, nifedipine, verapamil Plasma concentrations may be decreased. Appropriate doses for these combinations have not been established.
Cancer chemotherapy: Cyclophosphamide Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Ergot alkaloids: Ergotamine Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Immunosuppressants: Cyclosporine, tacrolimus, sirolimus Plasma concentrations may be decreased. Appropriate doses for these combinations have not been established.
Motility agents: Cisapride Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Opiate agonists: Fentanyl Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Oral contraceptives:
Ethinyl estradiol and Norethindrone*
↓ Ethinyl estradiol
↓ Norethindrone
Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended.
* The interaction between Nevirapine and the drug was evaluated in a clinical study. All other drug interactions shown are predicted.


Table name:
Table II. Clinically significant drug interactions with theophylline*.
*     Refer to PRECAUTIONS , Drug Interactions for further information regarding table.
**   Average effect on steady state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.
Drug Type of Interaction Effect**
Adenosine Theophylline blocks adenosine receptors. Higher doses of adenosine may be required to achieve desired effect.
Alcohol A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours. 30% increase
Allopurinol Decreases theophylline clearance at allopurinol doses ≥ 600 mg/day. 25% increase
Aminoglutethimide Increases theophylline clearance by induction of microsomal enzyme activity. 25% decrease
Carbamazepine Similar to aminoglutethimide. 30% decrease
Cimetidine Decreases theophylline clearance by inhibiting cytochrome P450 1A2. 70% increase
Ciprofloxacin Similar to cimetidine. 40% increase
Clarithromycin Similar to erythromycin. 25% increase
Diazepam Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram Decreases theophylline clearance by inhibiting hydroxylation and demethylation. 50% increase
Enoxacin Similar to cimetidine. 300% increase
Ephedrine Synergistic CNS effects. Increased frequency of nausea, nervousness, and insomnia.
Erythromycin Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3. 35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown. 30% increase
Flurazepam Similar to diazepam. Similar to diazepam.
Fluvoxamine Similar to cimetidine. Similar to cimetidine.
Halothane Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines. Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-A Decreases theophylline clearance. 100% increase
Isoproterenol (IV) Increases theophylline clearance. 20% decrease
Ketamine Pharmacologic May lower theophylline seizure threshold.
Lithium Theophylline increases renal lithium clearance. Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam Similar to diazepam. Similar to diazepam.
Methotrexate (MTX) Decreases theophylline clearance. 20% increase after low dose MTX, higher dose MTX may have a greater effect.
Mexiletine Similar to disulfiram. 80% increase
Midazolam Similar to diazepam. Similar to diazepam.
Moricizine Increases theophylline clearance. 25% decrease
Pancuronium Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition. Larger dose of pancuronium may be required to achieve neuromuscular blockade.
Pentoxifylline Decreases theophylline clearance. 30% increase
Phenobarbital Similar to aminoglutethimide. 25% decrease after two weeks of concurrent Phenobarbital.
Phenytoin Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption. Serum theophylline and phenytoin concentrations decrease about 40%.
Propafenone Decreases theophylline clearance and pharmacologic interaction. 40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Propranolol Similar to cimetidine and pharmacologic interaction. 100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Rifampin Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity. 20-40% decrease
Sulfinpyrazone Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline. 20% decrease
Tacrine Similar to cimetidine, also increases renal clearance of theophylline. 90% increase
Thiabendazole Decreases theophylline clearance. 190% increase
Ticlopidine Decreases theophylline clearance. 60% increase
Troleandomycin Similar to erythromycin. 33-100% increase depending on troleandomycin dose.
Verapamil Similar to disulfiram. 20% increase


Table name:
Interacting Drug
Interaction
Theophylline
Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin
Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents
Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin
Monitor phenytoin level (7)
Methotrexate
Monitor for methotrexate toxicity (7)
Cyclosporine
May increase serum creatinine. Monitor serum creatinine (7)
Multivalent cation- containing products including antacids, metal cations or didanosine
Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin (7)


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Table 18Summary of Effect of Coadministered Drugs on Exposure to Active Moiety(Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients withSchizophrenia
*Change relative to reference
Coadministered Drug
Dosing Schedule

Effect on Active
Moiety
(Risperidone + 9-
Hydroxy-
Risperidone (Ratio*)

Risperidone Dose
Recommendation

Coadministered Drug
Risperidone
AUC
C m a x

Enzyme (CYP2D6) 
Inhibitors 





Fluoxetine 
20 mg/day
2 or 3 mg twice
daily
1.4
1.5
Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine 
10 mg/day
4 mg/day
1.3
-
Re-evaluate dosing. 

20 mg/day
4 mg/day
1.6
-
Do not exceed 8 mg/day

40 mg/day
4 mg/day
1.8
-

Enzyme (CYP3A/ 
PgP inducers) 





Carbamazepine 
573 ± 168 mg/day
3 mg twice daily
0.51
0.55
Titrate dose upwards.
Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) 
Inhibitors 





Ranitidine 
150 mg twice daily
1 mg single dose
1.2
1.4
Dose adjustment not
needed
Cimetidine 
400 mg twice daily
1 mg single dose
1.1
1.3
Dose adjustment not
needed
Erythromycin 
500 mg four times
daily
1 mg single dose
1.1
0.94
Dose adjustment not
needed
Other Drugs 





Amitriptyline 
50 mg twice daily
3 mg twice daily
1.2
1.1
Dose adjustment not
needed


Table name:
Factors
Dosage  Adjustments  for  Aripiprazole  Tablets
Known CYP2D6 Poor Metabolizers
Administer half of usual dose
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors
Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors
Administer half of usual dose
Strong CYP2D6 and CYP3A4
inhibitors
Administer a quarter of usual dose
Strong CYP3A4 inducers
Double usual dose over 1 to 2 weeks


Table name:
Figure 1: Effect of interacting drugs on the pharmacokinetics of venlafaxine and active metabolite O-desmethylvenlafaxine (ODV).


Table name:
Table 3 Clinically Significant Drug Interactions with Meloxicam
Drugs  that  Interfere  with  Hemostasis 
Clinical  Impact
Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. 
Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. 
Intervention

Monitor patients with concomitant use of Meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin 
Clinical  Impact
Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].
Intervention

Concomitant use of Meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. Meloxicam is not a substitute for low dose aspirin for cardiovascular protection.
ACE  Inhibitors Angiotensin  Receptor  Blockers or  Beta - Blockers 
Clinical  Impact
NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). 
In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, coadministration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. 
Intervention

During concomitant use of Meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.  During concomitant use of Meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics 
Clinical  Impact
Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. 
Intervention

During concomitant use of Meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Lithium 
Clinical  Impact
NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [see Clinical Pharmacology (12.3)].
Intervention

During concomitant use of Meloxicam and lithium, monitor patients for signs of lithium toxicity. 
Methotrexate 
Clinical  Impact
Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). 
Intervention

During concomitant use of Meloxicam and methotrexate, monitor patients for methotrexate toxicity. 
Cyclosporine 
Clinical  Impact
Concomitant use of Meloxicam and cyclosporine may increase cyclosporine's nephrotoxicity. 
Intervention

During concomitant use of Meloxicam and cyclosporine, monitor patients for signs of worsening renal function. 
NSAIDs  and  Salicylates 
Clinical  Impact
Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention

The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended. 
Pemetrexed 
Clinical  Impact
Concomitant use of Meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). 
Intervention

During concomitant use of Meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. 

Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. 

In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended. 


Table name:
NA – Not available/reported
Digoxin concentrations increased greater than 50%
   Digoxin Serum   
Concentration Increase
   Digoxin AUC   
Increase
Recommendations
Amiodarone 70% NA Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring.
Captopril 58% 39%
Clarithromycin NA 70%
Dronedarone NA 150%
Gentamicin 129-212% NA
Erythromycin 100% NA
Itraconazole 80% NA
Lapatinib NA 180%
Propafenone NA 60-270%
Quinidine 100% NA
Ranolazine 50% NA
Ritonavir NA 86%
Telaprevir 50% 85%
Tetracycline 100% NA
Verapamil 50-75% NA
Digoxin concentrations increased less than 50%
Atorvastatin 22% 15% Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring.
Carvedilol 16% 14%
Conivaptan 33% 43%
Diltiazem 20% NA
Indomethacin 40% NA
Nefazodone 27% 15%
Nifedipine 45% NA
Propantheline 24% 24%
Quinine NA 33%
Rabeprazole 29% 19%
Saquinavir 27% 49%
Spironolactone      25% NA
Telmisartan 20-49% NA
Ticagrelor 31% 28%
Tolvaptan 30% 20%
Trimethoprim 22-28% NA
Digoxin concentrations increased, but magnitude is unclear
Alprazolam, azithromycin, cyclosporine, diclofenac, diphenoxylate, epoprostenol, esomeprazole, ibuprofen, ketoconazole, lansoprazole, metformin, omeprazole Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin concentrations decreased
Acarbose, activated charcoal, albuterol, antacids, certain cancer chemotherapy or radiation therapy, cholestyramine, colestipol, extenatide, kaolin-pectin, meals high in bran, metoclopramide, miglitol, neomycin, penicillamine, phenytoin, rifampin, St. John’s Wort, sucralfate, sulfasalazine Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20-40% as necessary.


Table name:
Bleeding times
Clinical Impact: Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention: This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact: The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention: Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact: Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention: This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.


Table name:
AED Coadministered AED Concentration Topiramate Concentration
Phenytoin
NC or 25% increase Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
48% decrease


Carbamazepine (CBZ)
NC
40% decrease
CBZ epoxide Is not administered but is an active metabolite of carbamazepine.
NC
NE
Valproic acid
11% decrease
14% decrease
Phenobarbital
NC
NE
Primidone
NC
NE
Lamotrigine
NC at TPM doses up to 400 mg/day
13% decrease


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T 4 and T 3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin/Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens/Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non-Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT 4 . Continued administration results in a decrease in serum T 4 and normal FT 4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T 4 and T 3 to TBG and transthyretin. An initial increase in serum FT 4 is followed by return of FT 4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T 4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T 4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ³ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T 4 to T 3, leading to decreased T 3 levels. However, serum T 4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T 3 and T 4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T 3 concentrations by 30% with minimal change in serum T 4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T 3 and T 4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias
and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123 I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 2. Drugs That May Decrease T4 Absorption (Hypothyroidism)
Potential impact: Concurrent use may reduce the efficacy of SYNTHROID by binding and delaying or preventing absorption, potentially resulting in hypothyroidism.
Drug or Drug Class Effect
Calcium Carbonate
Ferrous Sulfate
Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer SYNTHROID at least 4 hours apart from these agents.
Orlistat Monitor patients treated concomitantly with orlistat and SYNTHROID for changes in thyroid function.
Bile Acid Sequestrants
- Colesevelam
- Cholestyramine
- Colestipol
Ion Exchange Resins
- Kayexalate
- Sevelamer
Bile acid sequestrants and ion exchange resins are known to decrease levothyroxine absorption. Administer SYNTHROID at least 4 hours prior to these drugs or monitor TSH levels.
Other drugs:
Proton Pump Inhibitors
Sucralfate
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Gastric acidity is an essential requirement for adequate absorption of levothyroxine. Sucralfate, antacids and proton pump inhibitors may cause hypochlorhydria, affect intragastric pH, and reduce levothyroxine absorption. Monitor patients appropriately.


Table name:
 Interacting  Drug 
 Interaction 
 Multivalent cation-containing products including antacids, metal cations or didanosine 
 Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
 Warfarin 
 Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
 Antidiabetic agents 
 Carefully monitor blood glucose (5.11, 7.3)


Table name:
Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Drug Description
Corticosteroids Decreases plasma salicylate level; tapering doses of steroids may promote salicylism
Ammonium Sulfate Increases plasma salicylate level


Table name:
Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.Refer to PRECAUTIONS, Drug Interactions for information regarding table.
 albuterol,  famotidine  nizatidine
  systemic and inhaled  felodipine  norfloxacin
 amoxicillin  finasteride  ofloxacin
 ampicillin,  hydrocortisone  omeprazole
  with or without  isoflurane  prednisone, prednisolone
  sulbactam  isoniazid  ranitidine
 atenolol  isradipine  rifabutin
 azithromycin  influenza vaccine  roxithromycin
 caffeine,  ketoconazole  sorbitol
  dietary digestion  lomefloxacin  (purgative doses do not
 cefaclor  mebendazole  inhibit theophylline
 co-trimoxazole  medroxyprogesterone  absorption)
 (trimethoprim and  methylprednisolone  sucralfate
  sulfamethoxazole)  metronidazole  terbutaline, systemic
 diltiazem  metoprolol  terfenadine
 dirithromycin  nadolol  tetracycline
 enflurane  nifedipine  tocainide


Table name:
Factors Dosage Adjustment of ABILIFY
Known CYP2D6 Poor Metabolizers Administer half of usual dose
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors Administer half of usual dose
Strong CYP2D6 and CYP3A4 inhibitors Administer a quarter of usual dose
Strong CYP3A4 inducers Double usual dose over 1 to 2 weeks


Table name:
Table 6. Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology ( 12.3)]
Drug/Drug Class
(Mechanism of Interaction by the Drug)
Voriconazole Plasma Exposure
(C max and AUC τ after 200 mg q12h)
Recommendations for Voriconazole Dosage Adjustment/Comments
Rifampin Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg q12h voriconazole to healthy subjects and Rifabutin
(CYP450 Induction)
Significantly Reduced Contraindicated
Efavirenz (400 mg q 24h) Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects (CYP450 Induction) Efavirenz (300 mg q 24h) (CYP450 Induction) Significantly Reduced Slight decrease in AUC t Contraindicated When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)
(CYP450 Induction)
Significantly Reduced Contraindicated
Low-dose Ritonavir (100 mg q12h) (CYP450 Induction) Reduced Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Carbamazepine
(CYP450 Induction)
Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction Contraindicated
Long Acting Barbiturates
(CYP450 Induction)
Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction Contraindicated
Phenytoin
(CYP450 Induction)
Significantly Reduced Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg)
St. John’s Wort
(CYP450 inducer; P-gp inducer)
Significantly Reduced Contraindicated
Oral Contraceptives
containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)
Increased Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole (CYP2C9, CYP2C19 and CYP3A4 Inhibition) Significantly Increased Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole.
Other HIV Protease Inhibitors
(CYP3A4 Inhibition)
In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure
In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)
No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIs Non-Nucleoside Reverse Transcriptase Inhibitors (CYP3A4 Inhibition or CYP450 Induction) In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to voriconazole
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure) Careful assessment of voriconazole effectiveness


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may
result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-
   containing radiographic
   contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which
may result in hyperthyroidism
Amiodarone
Iodide (including iodine-
containing Radiographic
contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase Drugs that may decrease
serum TBG concentration serum TBG concentration
Clofibrate Androgens / Anabolic Steroids
Estrogen-containing oral Asparaginase
   contraceptives Glucocorticoids
Estrogens (oral) Slow-Release Nicotinic Acid
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal
Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake
Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
NITROPRUSSIDE
Para-aminosalicylate sodium
Perphenazine
Resorcinol
 (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 2 Rifabutin Interaction Studies
Coadministered drug Dosing regimen of coadministered drug Dosing regimen of rifabutin Study population (n) Effect on rifabutin Effect on coadministered drug Recommendation
↑ indicates increase; ↓ indicates decrease; ↔ indicates no significant change
QD- once daily; BID- twice daily; TID – thrice daily
ND - No Data
AUC - Area under the Concentration vs. Time Curve; Cmax - Maximum serum concentration
ANTIVIRALS
Amprenavir 1200 mg BID × 10 days 300 mg QD × 10 days Healthy male subjects (6) ↑ AUC by 193%,
↑ Cmax by 119%
Reduce rifabutin dose by at least 50%. Monitor closely for adverse reactions.
Delavirdine 400 mg TID 300 mg QD HIV-infected patients (7) ↑ AUC by 230%,
↑ Cmax by 128%
↓ AUC by 80%,
↓ Cmax by 75%,
↓ Cmin by 17%
CONTRAINDICATED
Didanosine 167 or 250 mg BID × 12 days 300 or 600 mg QD × 1 HIV-infected patients (11)
Fosamprenavir/ ritonavir 700 mg BID plus ritonavir 100 mg BID × 2 weeks 150 mg every other day × 2 weeks Healthy subjects (15) ↔ AUCcompared to rifabutin 300 mg QD alone
↓ Cmax by 15%
↑ AUC by 35%compared to historical control (fosamprenavir/ritonavir 700/100 mg BID),
↑ Cmax by 36%,
↑ Cmin by 36%,
Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with fosamprenavir/ritonavir combination.
Indinavir 800 mg TID × 10 days 300 mg QD × 10 days Healthy subjects (10) ↑ AUC by 173%,
↑ Cmax by 134%
↓ AUC by 34%,
↓ Cmax by 25%,
↓ Cmin by 39%
Reduce rifabutin dose by 50%, and increase indinavir dose from 800 mg to 1000 mg TID.
Lopinavir/ ritonavir 400/100 mg BID × 20 days 150 mg QD × 10 days Healthy subjects (14) ↑ AUC by 203% also taking zidovudine 500 mg QD
↓ Cmax by 112%
Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with lopinavir/ritonavir combination. Monitor closely for adverse reactions. Reduce rifabutin dosage further, as needed.
Saquinavir/ ritonavir 1000/100 mg BID × 14 or 22 days 150 mg every 3 days × 21–22 days Healthy subjects ↑ AUC by 53% compared to rifabutin 150 mg QD alone
↑ Cmax by 88%
(n=11)
↓ AUC by 13%,
↓ Cmax by 15%,
(n=19)
Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with saquinavir/ritonavir combination. Monitor closely for adverse reactions.
Ritonavir 500 mg BID × 10 days 150 mg QD × 16 days Healthy subjects (5) ↑ AUC by 300%,
↑ Cmax by 150%
ND Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with lopinavir/ritonavir combination. Monitor closely for adverse reactions.
Reduce rifabutin dosage further, as needed.
Tipranavir/ ritonavir 500/200 BID × 15 doses 150 mg single dose Healthy subjects (20) ↑ AUC by 190%,
↑ Cmax by 70%
Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with tipranavir/ritonavir combination. Monitor closely for adverse reactions. Reduce rifabutin dosage further, as needed.
Nelfinavir 1250 mg BID × 7–8 days 150 mg QD × 8 days HIV-infected patients (11) ↑ AUC by 83%, compared to rifabutin 300 mg QD alone
↑ Cmax by 19%
Reduce rifabutin dose by 50% (to 150 mg QD) and increase the nelfinavir dose to 1250 mg BID
Zidovudine 100 or 200 mg q4h 300 or 450 mg QD HIV-infected patients (16) ↓ AUC by 32%,
↓ Cmax by 48%,
Because zidovudine levels remained within the therapeutic range during coadministration of rifabutin, dosage adjustments are not necessary.
ANTIFUNGALS
Fluconazole 200 mg QD × 2 weeks 300 mg QD × 2 weeks HIV-infected patients (12) ↑ AUC by 82%,
↑ Cmax by 88%
Monitor for rifabutin associated adverse events. Reduce rifabutin dose or suspend MYCOBUTIN use if toxicity is suspected.
Posaconazole 200 mg QD × 10 days 300 mg QD × 17 days Healthy subjects (8) ↑ AUC by 72%,
↑ Cmax by 31%
↓ AUC by 49%,
↓ Cmax by 43%
If co-administration of these two drugs cannot be avoided, patients should be monitored for adverse events associated with rifabutin administration, and lack of posaconazole efficacy.
Itraconazole 200 mg QD 300 mg QD HIV-Infected patients (6) data from a case report ↓ AUC by 70%,
↓ Cmax by 75%,
If co-administration of these two drugs cannot be avoided, patients should be monitored for adverse events associated with rifabutin administration, and lack of itraconazole efficacy. In a separate study, one case of uveitis was associated with increased serum rifabutin levels following co-administration of rifabutin (300 mg QD) with itraconazole (600–900 mg QD).
Voriconazole 400 mg BID × 7 days (maintenance dose) 300 mg QD × 7 days Healthy male subjects (12) ↑ AUC by 331%,
↑ Cmax by 195%
↑ AUC by ~100%,
↑ Cmax by ~100%compared to voriconazole 200 mg BID alone
CONTRAINDICATED
ANTI-PCP (Pneumocystis carinii pneumonia)
Dapsone 50 mg QD 300 mg QD HIV-infected patients (16) ND ↓ AUC by 27 –40%
Sulfamethoxazole- Trimethoprim 800/160 mg 300 mg QD HIV-infected patients (12) ↓ AUC by 15–20%
ANTI-MAC (Mycobacterium avium intracellulare complex)
Azithromycin 500 mg QD × 1 day, then 250 mg QD × 9 days 300 mg QD Healthy subjects (6)
Clarithromycin 500 mg BID 300 mg QD HIV-infected patients (12) ↑ AUC by 75% ↓ AUC by 50% Monitor for rifabutin associated adverse events. Reduce dose or suspend use of MYCOBUTIN if toxicity is suspected. Alternative treatment for clarithromycin should be considered when treating patients receiving rifabutin
ANTI-TB (Tuberculosis)
Ethambutol 1200 mg 300 mg QD × 7 days Healthy subjects (10) ND
Isoniazid 300 mg 300 mg QD × 7 days Healthy subjects (6) ND
OTHER
Methadone 20 – 100 mg QD 300 mg QD × 13 days HIV-infected patients (24) ND
Ethinylestradiol (EE)/Norethindrone (NE) 35 mg EE / 1 mg NE × 21 days 300 mg QD × 10 days Healthy female subjects (22) ND EE: ↓ AUC by
35%, ↓ Cmax by 20%
NE: ↓ AUC by 46%
Patients should be advised to use additional or alternative methods of contraception.
Theophylline 5 mg/kg 300 mg × 14 days Healthy subjects (11) ND


Table name:
Table 3:   Drugs that Can Increase the Risk of Bleeding
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
NA = Not available/reported
Digoxin concentrations increased greater than 50%
   Digoxin Serum   
Concentration Increase
   Digoxin AUC Increase Recommendations
Amiodarone 70% NA Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring.
Captopril 58% 39%
Clarithromycin NA 70%
Dronedarone NA 150%
Gentamicin 129-212% NA
Erythromycin 100% NA
Itraconazole 80% NA
Lapatinib NA 180%
Nitrendipine 57% 15%
Propafenone NA 60-270%
Quinidine 100% NA
Ranolazine 50% NA
Ritonavir NA 86%
Telaprevir 50% 85%
Tetracycline 100% NA
Verapamil 50-75% NA
Digoxin concentrations increased less than 50%
Atorvastatin 22% 15% Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring.
Carvedilol 16% 14%
Conivaptan 33% 43%
Diltiazem 20% NA
Indomethacin 40% NA
Nefazodone 27% 15%
Nifedipine 45% NA
Propantheline 24% 24%
Quinine NA 33%
Rabeprazole 29% 19%
Saquinavir 27% 49%
Spironolactone      25% NA
Telmisartan 20-49% NA
Ticagrelor 31% 28%
Tolvaptan 30% 20%
Trimethoprim 22-28% NA
Digoxin concentrations increased, but magnitude is unclear
Alprazolam, azithromycin, cyclosporine, diclofenac, diphenoxylate, epoprostenol, esomeprazole, ibuprofen, ketoconazole, lansoprazole, metformin, omeprazole Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin concentrations decreased
Acarbose, activated charcoal, albuterol, antacids, certain cancer chemotherapy or radiation therapy, cholestyramine, colestipol, extenatide, kaolin-pectin, meals high in bran, metoclopramide, miglitol, neomycin, penicillamine, phenytoin, rifampin, St. John’s Wort, sucralfate and sulfasalazine Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20-40% as necessary.


Table name:
DRUG DESCRIPTION OF INTERACTION
Corticosteroids Decreases plasma salicylate level; tapering doses of steroids may promote salicylism.
Acidifying Agents Increases plasma salicylate level.
Alkalizing Agents Decreased plasma salicylate levels.


Table name:
Table 3. Drugs That May Alter T4 and Triiodothyronine (T3) Serum Transport Without Affecting Free Thyroxine (FT4) Concentration (Euthyroidism)
Drug or Drug Class Effect
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
These drugs may increase serum thyroxine-binding globulin (TBG) concentration.
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
These drugs may decrease serum TBG concentration.
Potential impact (below): Administration of these agents with SYNTHROID results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations.
Salicylates (> 2 g/day) Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total T4 levels may decrease by as much as 30%.
Other drugs:
Carbamazepine
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non-Steroidal Anti-inflammatory Drugs
- Fenamates
These drugs may cause protein-binding site displacement. Furosemide has been shown to inhibit the protein binding of T4 to TBG and albumin, causing an increase free T4 fraction in serum. Furosemide competes for T4-binding sites on TBG, prealbumin, and albumin, so that a single high dose can acutely lower the total T4 level. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total and free T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. Closely monitor thyroid hormone parameters.


Table name:
Table 3Drugs that Can Increase the Risk of Bleeding
Drug  Class
Specific  Drugs
Anticoagulants 
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin 
Antiplatelet Agents 
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine 
Nonsteroidal Anti-Inflammatory Agents 
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac 
Serotonin Reuptake Inhibitors 
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone 


Table name:
Table 7: Effect of Voriconazole on Pharmacokinetics of Other Drugs [see Clinical Pharmacology (12.3)]
*  Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects
** Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects
*** Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for 4 days voriconazole to subjects receiving a methadone maintenance dose (30-100 mg q24h)
****  Non-Steroidal Anti-Inflammatory Drug
***** Non-Nucleoside Reverse Transcriptase Inhibitors
Drug/Drug Class
(Mechanism of Interaction by Voriconazole)

Drug Plasma Exposure
(Cmax and AUCτ)
Recommendations for Drug Dosage Adjustment/Comments
Sirolimus*
(CYP3A4 Inhibition)
Significantly Increased
Contraindicated
Rifabutin*
(CYP3A4 Inhibition)
Significantly Increased
Contraindicated
Efavirenz (400 mg q24h)** (CYP3A4 Inhibition)
 
Efavirenz (300 mg q24h)** (CYP3A4 Inhibition)
 
Significantly  Increased
 
 
Slight Increase inAUCτ
Contraindicated
 
 
When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)** (CYP3A4 Inhibition)

Low-dose Ritonavir (100 mg q12h)**
No Significant Effect of Voriconazole on Ritonavir Cmax or AUCτ

Slight Decrease in Ritonavir Cmax and AUCτ
Contraindicated because of significant reduction of voriconazole Cmax and AUCτ


Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole Cmax and AUCτ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (CYP3A4 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased
Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids
(CYP450 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased
Contraindicated
Cyclosporine*
(CYP3A4 Inhibition)
AUCτ Significantly Increased; No Significant Effect on Cmax
When initiating therapy with voriconazole tablets in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When voriconazole tablets are discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
Methadone*** (CYP3A4 Inhibition)
Increased
Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl
(CYP3A4 Inhibition)
Increased
Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazoletablets. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7)]
Alfentanil
(CYP3A4 Inhibition)
Significantly Increased
Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with voriconazole tablet. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [see Drug Interactions (7)].
Oxycodone
(CYP3A4 Inhibition)
Significantly Increased
Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazoletablets. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7)].
NSAIDs**** including ibuprofen and diclofenac
(CYP2C9 Inhibition) 
Increased
Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed [see Drug Interactions (7)].
Tacrolimus*
(CYP3A4 Inhibition) 
Significantly Increased 
When initiating therapy with voriconazole tablets in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazoletablets are discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin*
(CYP2C9 Inhibition)
Significantly Increased
Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone
(CYP3A4 Inhibition)**
Increased
Monitoring for adverse events related to oral contraceptives is recommended during coadministration.
Warfarin*
(CYP2C9 Inhibition)
Prothrombin Time Significantly Increased
Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed.
Omeprazole*
(CYP2C19/3A4 Inhibition)
Significantly Increased
When initiating therapy with voriconazoletablets in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors
(CYP3A4 Inhibition)
In Vivo Studies Showed No Significant Effects on Indinavir Exposure
 
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)
No dosage adjustment for indinavir when coadministered with voriconazole tablets
 
 
Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors
Other NNRTIs***** (CYP3A4 Inhibition)
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity related to NNRTI
Benzodiazepines
(CYP3A4 Inhibition)
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.
HMG-CoA Reductase Inhibitors (Statins)
(CYP3A4 Inhibition)
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers
(CYP3A4 Inhibition)
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics
(CYP2C9 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased
Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids (CYP3A4 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased
Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed.
Everolimus
(CYP3A4 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased
Concomitant administration of
voriconazole and everolimus is not recommended. 


Table name:
CYP2C19 or CYP3A4 Inducers
Clinical Impact: Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology (12.3)].
Intervention: St. John’s Wort, rifampin: Avoid concomitant use with omeprazole [see Warnings and Precautions (5.9)]. Ritonavir-containing products: see prescribing information for specific drugs.
CYP2C19 or CYP3A4 Inhibitors
Clinical Impact: Increased exposure of omeprazole [see Clinical Pharmacology (12.3)].
Intervention: Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered. See prescribing information for voriconazole.


Table name:
Drugs That are Affected by Ciprofloxacin
Drug(s)
Recommendation
Comments
Tizanidine
Contraindicated
Concomitant administration of tizanidine and ciprofloxacin  is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)].
Theophylline
Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)
Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions (5.9)].
Drugs Known to Prolong QT Interval
Avoid Use
 
Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.11) and Use in Specific Populations (8.5)].
Oral antidiabetic drugs
Use with caution Glucose-lowering effect potentiated
Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs [see Adverse Reactions (6.1)].
Phenytoin
Use with caution Altered serum levels of phenytoin
(increased and decreased)
 
To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin with phenytoin.
Cyclosporine
Use with caution (transient elevations in serum creatinine)
Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs
Use with caution (Increase in anticoagulant effect)
The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate
Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels
Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole
Use with caution
Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin [see Warnings and Precautions (5.16)].
Clozapine
Use with caution
Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs
Use with caution
Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil
Use with caution Two-fold increase in exposure
Monitor for sildenafil toxicity [see Clinical Pharmacology (12.3)].
Duloxetine
Avoid Use
Five-fold increase in duloxetine exposure
If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives
Use with caution Reduced clearance resulting in elevated levels and prolongation
of serum half-life
Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx® (didanosine) chewable/ buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)
Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2.4)].
Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid
Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)
Potentiation of ciprofloxacin toxicity may occur.


Table name:
Antibiotics Antineo-plastic Antifungals Anti-inflammatory Drugs Gastro-intestinal 
Agents
Immuno-suppres-
sives
 
Other Drugs
ciprofloxacin gentamicin tobramycin trimethoprim with sulfamethoxazole vancomycin melphalan amphotericin B ketoconazole azapropazon colchicine diclofenac naproxen sulindac cimetidine ranitidine tacrolimus fibric acid
derivatives (e.g., bezafibrate, 
fenofibrate) methotrexate


Table name:
Name of the Concomitant
Drug
Change in the Concentration of Ganciclovir or Concomitant Drug Clinical Comment
Zidovudine ↓ Ganciclovir
↑ Zidovudine
Zidovudine and valganciclovir  each have the potential to cause neutropenia and anemia
Probenecid ↑ Ganciclovir Patients taking probenecid and valganciclovir  should be monitored for evidence of ganciclovir toxicity
Mycophenolate Mofetil (MMF) ↔ Ganciclovir (in patients with normal renal function)
↔ MMF (in patients with normal renal function)
Patients with renal impairment should be monitored carefully as levels of MMF metabolites and ganciclovir may increase
Didanosine ↓ Ganciclovir
↑ Didanosine
Patients should be closely monitored for didanosine toxicity


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide

Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide






Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T and T levels and increase TSH, although all values remain within normal limits in most patients. 4 3
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate










Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
  Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration   Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen





Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid


Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)





Administration of these agents with levothyroxine results in an initial transient increase in FT . Continued administration results in a decrease in serum T and normal FT and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T and T to TBG and transthyretin. An initial increase in serum FT , is followed by return of FT to normal levels with sustained therapeutic serum salicylate concentrations, although total-T levels may decrease by as much as 30%. 4 4 4 4 3 4 4 4
  Drugs that may alter T 4 and T 3 metabolism
  Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin


Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. 4
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)




Administration of these enzyme inhibitors decrease the peripheral conversion of T to T , leading to decreased T levels. However, serum T levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T and T levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T concentrations by 30% with minimal change in serum T levels. However, long-term glucocorticoid therapy may result in slightly decreased T and T levels due to decreased TBG production (see above). 4 3 3 4 3 4 3 4 3 4
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives

Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)


Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin




Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2

Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin

Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of I, I, and Tc. 123 131 99m
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics









These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme
Inhibitors
Inducers
CYP2C9 
amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast
aprepitant, bosentan, carbamazepine, phenobarbital, rifampin 
CYP1A2 
acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton
montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking 
CYP3A4 
alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton
armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide 


Table name:
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Do not exceed 40 mg atorvastatin daily


Table name:
Name of the Concomitant Drug Change in the Concentration of Ganciclovir or Concomitant Drug Clinical Comment
Zidovudine ↓ Ganciclovir
↑ Zidovudine
Zidovudine and valganciclovir  each have the potential to cause neutropenia and anemia
Probenecid ↑ Ganciclovir Patients taking probenecid and valganciclovir  should be monitored for evidence of ganciclovir toxicity
Mycophenolate Mofetil (MMF) ↔ Ganciclovir (in patients with normal renal function)
↔ MMF (in patients with normal renal function)
Patients with renal impairment should be monitored carefully as levels of MMF metabolites and ganciclovir may increase
Didanosine ↓ Ganciclovir
↑ Didanosine
Patients should be closely monitored for didanosine toxicity


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ Lamotrigine Decreased Lamotrigine levels approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide ↓ Lamotrigine Addition of carbamazepine decreases Lamotrigine concentration approximately 40%.
? CBZ epoxide May increase CBZ epoxide levels.
Phenobarbital/Primidone ↓ Lamotrigine Decreased Lamotrigine concentration approximately 40%.
Phenytoin (PHT) ↓ Lamotrigine Decreased Lamotrigine concentration approximately 40%.
Rifampin ↓ Lamotrigine Decreased Lamotrigine AUC approximately 40%.
Valproate ↑ Lamotrigine Increased Lamotrigine concentrations slightly more than 2-fold.
? valproate Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
Bleeding times
Clinical Impact: Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention: This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact: The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention: Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact: Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention: This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.  


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.12, 7.3)


Table name:
Table 4: Summary of AED Interactions with Topiramate
 AED
Coadministered
 AED
Concentration
 Topiramate
Concentration
 Phenytoin  NC or 25% increasePlasma concentration increased 25% in some patients, generally those on a b.i.d. dosing regimen of phenytoin  48% decrease
 Carbamazepine (CBZ)  NC  40% decrease
 CBZ epoxideIs not administered but is an active metabolite of carbamazepine  NC  NE
 Valproic acid  11% decrease  14% decrease
 Phenobarbital  NC  NE
 Primidone  NC  NE
 Lamotrigine  NC at TPM doses up to 400 mg/day  15% increase
 NC = Less than 10% change in plasma concentration
AED = Antiepileptic drug
NE = Not Evaluated
TPM = Topiramate


Table name:
Drugs that Affect Renal Function
A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDS], COX-2 inhibitors may impair the excretion of digoxin.
Antiarrthymics
Dofetilide
Concomitant administration with digoxin was associated with  a higher rate of torsades de pointes
Sotalol
Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
Dronedarone
Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone Analog
Teriparatide
Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement
Thyroid Supplement
Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics
Epinephrine
Norepinephrine
Dopamine
Can increase the risk of cardiac arrhythmias
Neuromuscular Blocking Agents
Succinylcholine
May cause sudden extrusion of potassium from muscle cells causing arrhythmias inpatients taking digoxin.
Supplements
Calcium
If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.
Hyperpolarization-activated cyclic nucleotide-gated channel blocker  Ivabradine Can increase the risk of bradycardia.


Table name:
Table 2: Clinically Significant Drug Interactions with Tramadol Hydrochloride Extended-Release Tablets
Inhibitors  of  CYP2D6
Clinical  Impact :
The concomitant use of tramadol hydrochloride extended-release tablets and CYP2D6 inhibitors may result in an increase in the plasma concentration of tramadol and a decrease in the plasma concentration of M1, particularly when an inhibitor is added after a stable dose of tramadol hydrochloride extended-release tablets is achieved. Since M1 is a more potent µ-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome.

After stopping a CYP2D6 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease and the M1 plasma concentration will increase which could increase or prolong therapeutic effects but also increase adverse reactions related to opioid toxicity, and may cause potentially fatal respiratory depression [ see  Clinical  Pharmacology  ( 12 . 3)].
Intervention :
If concomitant use of a CYP2D6 inhibitor is necessary, follow patients closely for adverse reactions including opioid withdrawal, seizures, and serotonin syndrome.

If a CYP2D6 inhibitor is discontinued, consider lowering tramadol hydrochloride extended-release tablets dosage until stable drug effects are achieved. Follow patients closely for adverse events including respiratory depression and sedation.
Examples
Quinidine, fluoxetine, paroxetine and bupropion
Inhibitors  of  CYP3A4
Clinical  Impact :
The concomitant use of tramadol hydrochloride extended-release tablets and CYP3A4 inhibitors can increase the plasma concentration of tramadol and may result in a greater amount of metabolism via CYP2D6 and greater levels of M1. Follow patients closely for increased risk of serious adverse events including seizures and serotonin syndrome, and adverse reactions related to opioid toxicity including potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of tramadol hydrochloride extended-release tablets is achieved.

After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease [ see  Clinical  Pharmacology  ( 12 . 3)], resulting in decreased opioid efficacy and possibly signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol.
Intervention :
If concomitant use is necessary, consider dosage reduction of tramadol hydrochloride extended-release tablets until stable drug effects are achieved. Follow patients closely for seizures and serotonin syndrome, and signs of respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the tramadol hydrochloride extended-release tablets dosage until stable drug effects are achieved and follow patients for signs and symptoms of opioid withdrawal.
Examples
Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)
CYP3A4  Inducers
Clinical  Impact :
The concomitant use of tramadol hydrochloride extended-release tablets and CYP3A4 inducers can decrease the plasma concentration of tramadol [ see  Clinical  Pharmacology  ( 12 . 3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to tramadol, [ see  Warnings  and  Precautions  ( 5 . 4)].
After stopping a CYP3A4 inducer, as the effects of the inducer decline, the tramadol plasma concentration will increase [ see  Clinical  Pharmacology  ( 12 . 3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause seizures and serotonin syndrome, and potentially fatal respiratory depression.
Intervention :
If concomitant use is necessary, consider increasing the tramadol hydrochloride extended-release tablets dosage until stable drug effects are achieved. Follow patients for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider tramadol hydrochloride extended-release tablets dosage reduction and monitor for seizures and serotonin syndrome, and signs of sedation and respiratory depression.

Patients taking carbamazepine, a CYP3A4 inducer, may have a significantly reduced analgesic effect of tramadol. Because carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of tramadol hydrochloride extended-release tablets and carbamazepine is not recommended.
Examples :
Rifampin, carbamazepine, phenytoin
Benzodiazepines  and  Other  Central  Nervous  System  ( CNS Depressants
Clinical  Impact :
Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention :
Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [ see  Warnings  and  Precautions  ( 5 . 5)].
Examples :
Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic  Drugs
Clinical  Impact :
The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention :
If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue tramadol hydrochloride extended-release tablets if serotonin syndrome is suspected.
Examples :
Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine  Oxidase  Inhibitors  ( MAOIs )
Clinical  Impact :
MAOI interactions with opioids may manifest as serotonin syndrome [ see  Warnings  and  Precautions  ( 5 . 6 )] or opioid toxicity (e.g., respiratory depression, coma) [ see  Warnings  and  Precautions  ( 5 . 2)].
Intervention :
Do not use tramadol hydrochloride extended-release tablets in patients taking MAOIs or within 14 days of stopping such treatment.
Examples :
phenelzine, tranylcypromine, linezolid
Mixed  Agonist / Antagonist  and  Partial  Agonist  Opioid  Analgesics
Clinical  Impact :
May reduce the analgesic effect of tramadol hydrochloride extended-release tablets and/or precipitate withdrawal symptoms.
Intervention :
Avoid concomitant use.
Examples :
butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle  Relaxants
Clinical  Impact :
Tramadol may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention :
Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of tramadol hydrochloride extended-release tablets and/or the muscle relaxant as necessary.
Diuretics
Clinical  Impact :
Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention :
Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic  Drugs
Clinical  Impact :
The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention :
Monitor patients for signs of urinary retention or reduced gastric motility when tramadol hydrochloride extended-release tablets are used concomitantly with anticholinergic drugs.
Digoxin
Clinical  Impact :
Post-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity.
Intervention :
Follow patients for signs of digoxin toxicity and adjust the dosage of digoxin as needed.
Warfarin
Clinical  Impact :
Post-marketing surveillance of tramadol has revealed rare reports of alteration of warfarin effect, including elevation of prothrombin times.
Intervention :
Monitor the prothrombin time of patients on warfarin for signs of an interaction and adjust the dosage of warfarin as needed.


Table name: ContraindicatedAvoid UseUse with cautionUse with cautionUse with caution
Drugs That are Affected by CIPRO
Drug(s) Recommendation Comments
Tizanidine
 
Concomitant administration of tizanidine and CIPRO is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)]
Theophylline Avoid Use (Plasma Exposure Likely to be Increased and Prolonged) Concurrent administration of CIPRO with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions (5.9)].
Drugs Known to Prolong QT Interval
 
CIPRO may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.11) and Use in Specific Populations (8.5)].
Oral antidiabetic drugs Use with caution Glucose-lowering effect potentiated Hypoglycemia sometimes severe has been reported when CIPRO and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when CIPRO is co-administered with oral antidiabetic drugs [see Adverse Reactions (6.1)].
Phenytoin Use with caution Altered serum levels of phenytoin (increased and decreased) To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon CIPRO discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of CIPRO with phenytoin.
Cyclosporine Use with caution (transient elevations in serum creatinine) Monitor renal function (in particular serum creatinine) when CIPRO is co-administered with cyclosporine.
Anti-coagulant drugs Use with caution (Increase in anticoagulant effect) The risk may vary with the underlying infection, age and general status of the patient so that the contribution of CIPRO to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of CIPRO with an oral anti-coagulant (for example, warfarin).
Methotrexate Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant CIPRO therapy is indicated.
Ropinirole
 
Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with CIPRO [see Warnings and Precautions (5.16)].
Clozapine
 
Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with CIPRO are advised.
NSAIDs
 
Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil Use with caution Two-fold increase in exposure Monitor for sildenafil toxicity [see Clinical Pharmacology (12.3 )].
Duloxetine Avoid Use Five-fold increase in duloxetine exposure If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life CIPRO inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of CIPRO
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products) CIPRO should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2.4)]. Decrease CIPRO absorption, resulting in lower serum and urine levels
Probenecid Use with caution (interferes with renal tubular secretion of CIPRO and increases CIPRO serum levels) Potentiation of CIPRO toxicity may occur.


Table name:
Drugs That Interfere with Hemostasis
Clinical Impact: Indomethacin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of indomethacin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of indomethacin with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ see Warnings and Precautions ( 5.11 )].
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ see Warnings and Precautions ( 5.2 ) ].
Intervention: Concomitant use of indomethacin capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions ( 5.11 )].Indomethacin is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: During concomitant use of indomethacin capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.During concomitant use of indomethacin capsules and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ see Warnings and Precautions ( 5.6 )].When these drugs are administered concomitantly, patients should be adequately hydrated.  Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.It has been reported that the addition of triamterene to a maintenance schedule of Indomethacin resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin and triamterene should not be administered together.Both indomethacin and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently [ see Warnings and Precautions ( 5.6 )].  
Intervention: Indomethacin and triamterene should not be administered together. During concomitant use of indomethacin capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects. Be aware that indomethacin and potassium-sparing diuretics may both be associated with increased serum potassium levels. [ see Warnings and Precautions ( 5.6 )].  
Digoxin  
Clinical Impact: The concomitant use of indomethacin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.  
Intervention: During concomitant use of indomethacin capsules and digoxin, monitor serum digoxin levels.  
Lithium  
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.  
Intervention: During concomitant use of indomethacin capsules and lithium, monitor patients for signs of lithium toxicity.  
Methotrexate  
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).  
Intervention: During concomitant use of indomethacin capsules and methotrexate, monitor patients for methotrexate toxicity.  
Cyclosporine  
Clinical Impact: Concomitant use of indomethacin capsules and cyclosporine may increase cyclosporine's nephrotoxicity.  
Intervention: During concomitant use of indomethacin capsules and cyclosporine, monitor patients for signs of worsening renal function.  
NSAIDs and Salicylates  
Clinical Impact: Concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ see Warnings and Precautions ( 5.2 )]. Combined use with diflunisal may be particularly hazardous because diflunisal causes significantly higher plasma levels of indomethacin [see Clinical Pharmacology ( 12.3 )].In some patients, combined use of indomethacin and diflunisal has been associated with fatal gastrointestinal hemorrhage.  
Intervention: The concomitant use of indomethacin with other NSAIDs or salicylates, especially diflunisal, is not recommended.  
Pemetrexed  
Clinical Impact: Concomitant use of indomethacin capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).  
Intervention: During concomitant use of indomethacin capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.  
Probenecid  
Clinical Impact: When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased.  
Intervention: During the concomitant use of indomethacin and probenecid, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect.  When increases in the dose of indomethacin are made, they should be made carefully and in small increments.  


Table name:
Antiarrhythmics Dofetilide Concomitant administration with digoxin was associated with a higher rate of torsades de pointes.
Moricizine Reported to increase PR interval and QRS duration. There are reports of first degree atrioventricular block or bundle branch block developing with digitalis administration. The known effects of moricizine on calcium conductance may explain the effects on atrioventricular node conduction.
Sotalol Proarrhythmic events even more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving dioxin.
Parathyroid Hormone Analog Teriparatide Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid Supplement Thyroid Treatment of hyperthyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics Epinepherine Can increase the risk of cardiac arrhythmias.
Norepinephrine
Dopamine
Neuromuscular Blocking Agents Succinylcholine May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.
Supplements Calcium If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers Additive effects on AV node conduction can result in complete heart block.


Table name:
AED Co-administered
AED Concentration
Topiramate Concentration
Phenytoin
NCor25%increasea
48%decrease
Carbamazepine(CBZ)
NC
40%decrease
CBZepoxideb
NC 
            NE
Valproic acid
11%decrease
14%decrease
Phenobarbital
NC
            NE
Primidone
NC
           NE
Lamotrigine
NCatTPM dosesupto400  mg/day 
         13%decrease


Table name:
Bleeding times
Clinical Impact: Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention: This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact: The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention: Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact: Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention: This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.


Table name: 250 mg (adults weighing at least 60 kg with creatinine clearance of at least 60 mL/min) 200 mg (adults weighing less than 60 kg with creatinine clearance of at least 60 mL/min)Patients should be monitored for didanosine-associated toxicities and clinical response.
Table 5: Established Drug Interactions Based on Studies with Didanosine Delayed-Release Capsules or Studies with Buffered Formulations of Didanosine and Expected to Occur with Didanosine Delayed-Release Capsules
Drug Effect Clinical Comment
ganciclovir ↑didanosine concentration If there is no suitable alternative to ganciclovir, then use in combination with didanosine delayed-release capsules with caution. Monitor for didanosine-associated toxicity.
methadone ↓didanosine concentration If coadministration of methadone and didanosine is necessary, the recommended formulation of didanosine is didanosine delayed-release capsules. Patients should be closely monitored for adequate clinical response when didanosine delayed-release capsules are coadministered with methadone, including monitoring for changes in HIV RNA viral load. Do not coadminister methadone with didanosine pediatric powder due to significant decreases in didanosine concentrations.
nelfinavir No interaction 1 hour after didanosine Administer nelfinavir 1 hour after didanosine delayed-release capsules.
tenofovir disoproxil fumarate ↑didanosine concentration A dose reduction of didanosine delayed-release capsules to the following dosage once daily taken together with tenofovir disoproxil fumarate and a light meal (400 kcalories or less and 20% fat or less) or in the fasted state is recommended.Coadministration of didanosine with food decreases didanosine concentrations. Thus, although not studied, it is possible that coadministration with heavier meals could reduce didanosine concentrations further.
↑ Indicates increase. ↓ Indicates decrease.


Table name:
Table 1: Clinically Significant Drug Interactions with Naproxen
Drugs That Interfere with Hemostasis
Clinical Impact: Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of naproxen tablets with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: Concomitant use of naproxen tablets and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen tablets are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: During concomitant use of naproxen tablets and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of naproxen tablets and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention During concomitant use of naproxen tablets with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact: The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of naproxen tablets and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen tablets and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of naproxen tablets and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of naproxen tablets and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of naproxen tablets and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of naproxen tablets and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of naproxen tablets and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact: Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention: Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen tablets are not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen tablets are not recommended.
Cholestyramine
Clinical Impact: Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention: Concomitant administration of cholestyramine with naproxen tablets are not recommended.
Probenecid
Clinical Impact: Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention: Patients simultaneously receiving naproxen tablets and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact: Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention: Patients simultaneously receiving naproxen tablets and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.


Table name:
Table 5 Effects on steady-state fexofenadine pharmacokinetics after 7 days of co-administration with fexofenadine hydrochloride 120 mg every 12 hours in healthy adult subjects (n=24)
Concomitant Drug CmaxSS
(Peak plasma concentration)
AUCss(0-12h)
(Extent of systemic exposure)
Erythromycin
(500 mg every 8 hrs)
+82% +109%
Ketoconazole
(400 mg once daily)
+135% +164%


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Table 4. Selected Drugs that are contraindicated for use with itraconazoleThis list is not all-inclusive.
Antipsychotics pimozide
Antiarrhythmics dofetilide, quinidine
Benzodiazepines oral midazolamFor information on parenterally administered midazolam, see the Benzodiazepine paragraph below., triazolam
Calcium Channel Blockers Nisoldipine, felodipine
Ergot Alkaloids dihydroergotamine, ergotamine, ergometrine (ergonovine), methylergometrine (methylergonovine)
Gastrointestinal Motility Agents cisapride
HMG CoA-Reductase Inhibitors lovastatin, simvastatin
Opiate Analgesics levacetylmethadol (levomethadyl), methadone


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may
result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-
   containing radiographic
   contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which
may result in hyperthyroidism
Amiodarone
Iodide (including iodine-
containing Radiographic
contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase Drugs that may decrease
serum TBG concentration serum TBG concentration
Clofibrate Androgens / Anabolic Steroids
Estrogen-containing oral Asparaginase
   contraceptives Glucocorticoids
Estrogens (oral) Slow-Release Nicotinic Acid
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal
Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake
Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
NITROPRUSSIDE
Para-aminosalicylate sodium
Perphenazine
Resorcinol
 (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme
Inhibitors
Inducers
CYP2C9 
amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast
aprepitant, bosentan, carbamazepine, phenobarbital, rifampin 
CYP1A2 
acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton
montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking 
CYP3A4 
alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton
armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide 


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant  Drug
Effect  on  Concentration  of  Lamotrigine  or 
Concomitant  Drug
Clinical  Comment 
↓= Decreased (induces lamotrigine gluronidation).
↑= Increased (inhibits lamotrigine glucuronidation).
?= Conflicting data.
Estrogen-containing oral 
contraceptive preparations 
containing 30 mcg ethinylestradiol 
and 150 mcg levonorgestrel
↓ lamotrigine




Decreased lamotrigine levels 
approximately 50%.




↓ levonorgestrel
Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and 
CBZ epoxide
↓ lamotrigine

Addition of carbamazepine decreases lamotrigine 
concentration approximately 40%.


? CBZ epoxide
May increase CBZ epoxide levels
Phenobarbital/Primidone
↓ lamotrigine
Decreased lamotrigine 
concentration approximately 40%.
Phenytoin (PHT)
↓ lamotrigine
Decreased lamotrigine 
concentration approximately 40%
Rifampin
↓ lamotrigine
Decreased lamotrigine AUC 
approximately 40%
Valproate
↑ lamotrigine

Increased lamotrigine concentrations slightly 
more than 2-fold.


? valproate
Decreased valproate concentrations an average of 
25% over a 3-week period then stabilized in healthy volunteers; 
no change in controlled clinical trials in epilepsy patients.



Table name:
Table 4: Clinically Important Drug Interactions with VIIBRYD
Concomitant Drug Name or Drug Class Clinical Rationale Clinical Recommendation
Monoamine Oxidase Inhibitors (MAOIs) The concomitant use of MAOIs and serotonergic drugs including VIIBRYD increases the risk of serotonin syndrome. VIIBRYD is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [see Contraindications (4), Dosage and Administration (2.3), and Warnings and Precautions (5.2)].
Other Serotonergic Drugs The concomitant use of serotonergic drugs including VIIBRYD and other serotonergic drugs increases the risk of serotonin syndrome. Monitor patients for signs and symptoms of serotonin syndrome, particularly during VIIBRYD initiation. If serotonin syndrome occurs, consider discontinuation of VIIBRYD and/or concomitant serotonergic drugs [see Warnings and Precautions (5.2)].
Antiplatelet Agents and Anticoagulants Serotonin release by platelets plays an important role in hemostasis. The concurrent use of an antiplatelet agent or anticoagulant with VIIBRYD may potentiate the risk of bleeding. Inform patients of the increased risk of bleeding with the concomitant use of VIIBRYD and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio (INR) when initiating or discontinuing VIIBRYD [see Warnings and Precautions (5.3)].
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin, voriconazole) The concomitant use of VIIBRYD and strong CYP3A4 inhibitors increased the exposure of vilazodone compared to the use of VIIBRYD alone [see Clinical Pharmacology (12.3)]. The VIIBRYD dose should not exceed 20 mg once daily with the concomitant use of a strong CYP3A4 inhibitor [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].
Strong CYP3A4 Inducers (e.g.,
carbamazepine, phenytoin, rifampin)
The concomitant use of VIIBRYD and strong CYP3A4 inducers decreased the exposure of vilazodone compared to the use of VIIBRYD alone [see Clinical Pharmacology (12.3)]. Based on clinical response, consider increasing the dosage of VIIBRYD, over 1 to 2 weeks in patients taking strong CYP3A4 inducers for greater than 14 days [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].
Digoxin Digoxin is a narrow therapeutic index drug. Concomitant use of VIIBRYD increased digoxin concentrations [see Clinical Pharmacology (12.3)]. Measure serum digoxin concentrations before initiating concomitant use of VIIBRYD. Continue monitoring and reduce digoxin dose as necessary.


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T 4 and T 3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin/Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens/Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non-Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT 4 . Continued administration results in a decrease in serum T 4 and normal FT 4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T 4 and T 3 to TBG and transthyretin. An initial increase in serum FT 4 is followed by return of FT 4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T 4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T 4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ³ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T 4 to T 3, leading to decreased T 3 levels. However, serum T 4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T 3 and T 4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T 3 concentrations by 30% with minimal change in serum T 4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T 3 and T 4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias
and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123 I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.11, 7.3)


Table name:
I. Due to the competition of salicylate with other drugs for binding to serum albumin the following drug interactions may occur:
DRUG DESCRIPTION OF INTERACTION
Sulfonylureas Hypoglycemia potentiated.
Methotrexate Decreases tubular reabsorption; clinical toxicity from methotrexate can result.
Oral Anticoagulants Increased bleeding.
II. Drugs changing salicylate levels by altering renal tubular reabsorption:
DRUG DESCRIPTION OF INTERACTION
Corticosteroids Decreases plasma salicylate level; tapering doses of steroids may promote salicylism.
Acidifying Agents Increases plasma salicylate levels.
Alkanizing Agents Decreased plasma salicylate levels.
III. Drugs with complicated interactions with salicylates:
DRUG DESCRIPTION OF INTERACTION
Heparin Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients.
Pyrazinamide Inhibits pyrazinamide-induced hyperuricemia.
Uricosuric Agents Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited.
The following alterations of laboratory tests have been reported during salicylate therapy:
LABORATORY TESTS EFFECT OF SALICYLATES
Thyroid Function Decreased PBI; increased t3 uptake.
Urinary Sugar False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5g q.d.).
5-Hydroxyindole acetic acid False negative with fluorometric test.
Acetone ketone bodies False positive FeCI3 in Gerhardt reaction; red color persists with boiling.
17-OH corticosteroids False reduced values with >4.8g q.d. salicylate.
Vanilmandelic acid False reduced values.
Uric Acid May increase or decrease depending on dose.
Prothrombin Decreased levels; slightly increased prothrombin time.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
 Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)  Avoid atorvastatin
 HIV protease inhibitor (lopinavir plus ritonavir)  Use with caution and lowest dose necessary
 Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir )  Do not exceed 20 mg atorvastatin daily
 HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
 Do not exceed 40 mg atorvastatin daily


Table name:
Interacting DrugInteracting Drug InteractionInteraction
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products (2.4, 7.1)
Warfarin
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents
Carefully monitor blood glucose (5.12, 7.3)


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7.1, 7.2, 7.3, 7.4)
Interacting Agents Prescribing Recommendations
   Itraconazole, ketoconazole, erythromycin, clarithromycin, 
   telithromycin, HIV protease inhibitors, nefazodone
   Avoid simvastatin
   Gemfibrozil, cyclosporine, danazol
   Do not exceed 10 mg simvastatin daily
   Amiodarone, verapamil
   Do not exceed 20 mg simvastatin daily
   Diltiazem    Do not exceed 40 mg simvastatin daily
   Grapefruit juice
   Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Table 3: Clinically Relevant Interactions Affecting Drugs Co-Administered with Omeprazole and Interaction with Diagnostics
Antiretrovirals
Clinical Impact:
The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology ( 12.3)]. Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see Clinical Pharmacology (12.3)]. There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole.
Intervention:
Rilpivirine-containing products: Concomitant use with omeprazole is contraindicated [see Contraindications ( 4)] .
 
Atazanavir: Avoid concomitant use with omeprazole. See prescribing information for atazanavir for dosing information.
 
Nelfinavir: Avoid concomitant use with omeprazole. See prescribing information for nelfinavir.
 
Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities.
 
Other antiretrovirals: See prescribing information for specific antiretroviral drugs.
Warfarin
Clinical Impact:
Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
Intervention:
Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range.
Methotrexate
Clinical Impact:
Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions ( 5.11)].
Intervention:
A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate.
CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam)
Clopidogrel
Clinical Impact:
Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology ( 12.3)].
There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel .
Intervention:
Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy [see Warnings and Precautions ( 5.6)].
Citalopram
Clinical Impact:
Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology ( 12.3)] .
Intervention:
Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.
Cilostazol
Clinical Impact:
Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology ( 12.3)].
Intervention:
Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.
Phenytoin
Clinical Impact:
Potential for increased exposure of phenytoin.
Intervention:
Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin.
Diazepam
Clinical Impact:
Increased exposure of diazepam [see Clinical Pharmacology ( 12.3)] .
Intervention:
Monitor patients for increased sedation and reduce the dose of diazepam as needed.
Digoxin
Clinical Impact:
Potential for increased exposure of digoxin [see Clinical Pharmacology ( 12.3)].
Intervention:
Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)
Clinical Impact:
Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
Intervention:
Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF [see Clinical Pharmacology ( 12.3)] .
 
See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact:
Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions.
Intervention:
See Contraindications, Warnings and Precautions  in prescribing information for clarithromycin.
 
See  Drug Interactions in prescribing information for amoxicillin.
Tacrolimus
Clinical Impact:
Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19 .
Intervention:
Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact:
Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions ( 5.10), Clinical Pharmacology ( 12.2)] .
Intervention:
Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
Interaction with Secretin Stimulation Test
Clinical Impact:
Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention:
Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology ( 12.2)] .
False Positive Urine Tests for THC
Clinical Impact:
There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.
Intervention:
An alternative confirmatory method should be considered to verify positive results.
Other
Clinical Impact:
There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram).
Intervention:
Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole.


Table name:
*Change relative to reference
Coadministered Drug
 
Dosing Schedule
Effect on Active Moiety
(Risperidone + 9- Hydroxy-
Risperidone (Ratio*)
Risperidone Dose
Recommendation
Coadministered Drug
Risperidone
AUC
Cmax
Enzyme (CYP2D6) inhibitors
 
 
 
 
Fluoxetine
20 mg/day
2 or 3 mg twice daily
1.4
1.5

Re-evaluate dosing.
Do not exceed 8 mg/day
Paroxetine
10 mg/day
4 mg/day
1.3
-

Re-evaluate dosing.
Do not exceed 8 mg/day
20 mg/day
4 mg/day
1.6
-
40 mg/day
4 mg/day
1.8
-
Enzyme (CYP3A/ PgP inducers) Inducers
 
 
 
 
 
Carbamazepine
573 ± 168 mg/day
 
3 mg twice daily
 
0.51
 
0.55
 

Titrate dose upwards.
Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) inhibitors
 
 
 
 
 
Ranitidine
150 mg twice daily
1 mg single dose
1.2
1.4
Dose adjustment not needed
Cimetidine
400 mg twice daily
1 mg single dose
1.1
1.3
Dose adjustment not needed
Erythromycin
500 mg four times daily
1 mg single dose
1.1
0.94
Dose adjustment not needed
Other Drugs
 
 
 
 
 
Amitriptyline
50 mg twice daily
3 mg twice daily
1.2
1.1
Dose adjustment not Needed


Table name:
Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug Dosing Schedule Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio Change relative to reference ) Risperidone Dose Recommendation
Coadministered Drug Risperidone AUC Cmax
Enzyme (CYP2D6) Inhibitors
Fluoxetine 20 mg/day 2 or 3 mg twice daily 1.4 1.5 Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine 10 mg/day 4 mg/day 1.3 - Re-evaluate dosing. Do not exceed 8 mg/day
20 mg/day 4 mg/day 1.6 -
40 mg/day 4 mg/day 1.8 -
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine 573 ± 168 mg/day 3 mg twice daily 0.51 0.55 Titrate dose upwards. Do not exceed twice the patient's usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine 150 mg twice daily 1 mg single dose 1.2 1.4 Dose adjustment not needed
Cimetidine 400 mg twice daily 1 mg single dose 1.1 1.3 Dose adjustment not needed
Erythromycin 500 mg four times daily 1 mg single dose 1.1 0.94 Dose adjustment not needed
Other Drugs
Amitriptyline 50 mg twice daily 3 mg twice daily 1.2 1.1 Dose adjustment not needed


Table name:
Drugs That Interfere with Hemostasis
Clinical Impact: • Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of naproxen or naproxen sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: Concomitant use of naproxen or naproxen sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen or naproxen sodium is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE-inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: • During concomitant use of naproxen or naproxen sodium and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of naproxen or naproxen sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen or naproxen sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact: The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of naproxen or naproxen sodium and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen or naproxen sodium and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of naproxen or naproxen sodium and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of naproxen or naproxen sodium and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of naproxen or naproxen sodium and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of naproxen or naproxen sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of naproxen or naproxen sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact: Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention: Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen or naproxen sodium is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed release tablets are not recommended.
Cholestyramine
Clinical Impact: Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention: Concomitant administration of cholestyramine with naproxen or naproxen sodium is not recommended.
Probenecid
Clinical Impact: Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention: Patients simultaneously receiving naproxen or naproxen sodium and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact: Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention: Patients simultaneously receiving naproxen or naproxen sodium and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine
Do not co-administer the intravenous formulation in the same IV line with an multivalent cation, e.g., magnesium (2.4 , 7.1)
Warfarin
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents
Carefully monitor blood glucose (5.12 , 7.3)


Table name:
Table 25: Clinically Important Drug Interactions with ABILIFY:
Concomitant Drug Name or Drug Class Clinical Rationale Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) The concomitant use of ABILIFY with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of ABILIFY alone [see CLINICAL PHARMACOLOGY (12.3)]. With concomitant use of ABILIFY with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the ABILIFY dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin) The concomitant use of ABILIFY and carbamazepine decreased the exposure of aripiprazole compared to the use of ABILIFY alone [see CLINICAL PHARMACOLOGY (12.3)]. With concomitant use of ABILIFY with a strong CYP3A4 inducer, consider increasing the ABILIFY dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Antihypertensive Drugs Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.7)].
Benzodiazepines (e.g., lorazepam) The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.7)] Monitor sedation and blood pressure. Adjust dose accordingly.


Table name:
Table 2Clinically Significant Drug Interactions with Indomethacin Drugs That Interfere with Hemostasis
Clinical  Impact
Indomethacin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant uses of indomethacin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. 
Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. 
Intervention
Monitor patients with concomitant use of indomethacin capsules with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see  Warnings  and  Precautions  ( 5 . 11)].
Aspirin

Clinical  Impact

Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see  Warnings  and  Precautions  ( 5 . 2)]. 
Intervention

Concomitant use of indomethacin capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see  Warnings  and  Precautions  ( 5 . 11)]. Indomethacin capsules are not a substitute for low dose aspirin for cardiovascular protection.
ACE  Inhibitors Angiotensin  Receptor  Blockers and  Beta - Blockers

Clinical  Impact

NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). 
In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. 
Intervention :
During concomitant use of indomethacin capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. 
During concomitant use of Indomethacin capsules and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see  Warnings  and  Precautions  ( 5 . 6)].
When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. 
Diuretics

Clinical  Impact

Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. 
It has been reported that the addition of triamterene to a maintenance schedule of Indomethacin capsules resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin capsules and triamterene should not be administered together. 
Both Indomethacin capsules and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin capsules and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently. 
Intervention

Indomethacin and triamterene should not be administered together. During concomitant use of indomethacin capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects. 
Be aware that indomethacin and potassium-sparing diuretics may both be associated with increased serum potassium levels [see  Warnings  and  Precautions  ( 5 . 6)]. 
Digoxin

Clinical  Impact

The concomitant use of indomethacin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. 
Intervention

During concomitant use of indomethacin capsules and digoxin, monitor serum digoxin levels. 
Lithium

Clinical  Impact

NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearanceThe mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention

During concomitant use of indomethacin capsules and lithium, monitor patients for signs of lithium toxicity. 
Methotrexate

Clinical  Impact

Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). 
Intervention

During concomitant use of indomethacin capsules and methotrexate, monitor patients for methotrexate toxicity. 
Cyclosporine

Clinical  Impact

Concomitant use of indomethacin capsules and cyclosporine may increase cyclosporine’s nephrotoxicity. 
Intervention

During concomitant use of indomethacin capsules and cyclosporine, monitor patients for signs of worsening renal function. 
NSAIDs  and  Salicylates

Clinical  Impact

Concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see  Warnings  and  Precautions  ( 5 . 2 )]. 
Combined use with diflunisal may be particularly hazardous because diflunisal causes significantly higher plasma levels of indomethacin. [see Clinical  Pharmacology  ( 12 . 3)]. 
In some patients, combined use of indomethacin and diflunisal has been associated with fatal gastrointestinal hemorrhage. 
Intervention

The concomitant use of indomethacin with other NSAIDs or salicylates, especially diflunisal, is not recommended. 
Pemetrexed

Clinical  Impact

Concomitant use of indomethacin capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). 
Intervention

During concomitant use of indomethacin capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. 
NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. 
In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. 
Probenecid

Clinical  Impact

When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased. 
Intervention

During the concomitant use of indomethacin capsules and probenecid, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect. When increases in the dose of indomethacin are made, they should be made carefully and in small increments. 


Table name:
Drug Name Effect on Concentration of Nevirapine or Concomitant Drug Clinical Comment
HIV Antiviral Agents: Protease Inhibitors (PIs)
Atazanavir/Ritonavir* ↓ Atazanavir
↑ Nevirapine
Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures.
Fosamprenavir* ↓ Amprenavir
↑ Nevirapine
Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.
Fosamprenavir/Ritonavir* ↓ Amprenavir

↑ Nevirapine
No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied.
Indinavir* ↓ Indinavir The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established.
Lopinavir/Ritonavir* ↓ Lopinavir Dosing in adult patients:

A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.
Nelfinavir* ↓ Nelfinavir M8 Metabolite
↓ Nelfinavir Cmin
The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established.
Saquinavir/ritonavir The interaction between nevirapine and saquinavir/ritonavir has not been evaluated. The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz* ↓ Efavirenz The appropriate doses of these combinations with respect to safety and efficacy have not been established.
Delavirdine
Etravirine
Rilpivirine
Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial.
Hepatitis C Antiviral Agents
Boceprevir Plasma concentrations of boceprevir may be decreased due to induction of CYP3A4/5 by nevirapine. Nevirapine and boceprevir should not be coadministered because decreases in boceprevir plasma concentrations may result in a reduction in efficacy.
Telaprevir Plasma concentrations of telaprevir may be decreased due to induction of CYP3A4 by nevirapine and plasma concentrations of nevirapine may be increased due to inhibition of CYP3A4 by telaprevir. Nevirapine and telaprevir should not be coadministered because changes in plasma concentrations of nevirapine, telaprevir, or both may result in a reduction in telaprevir efficacy or an increase in nevirapine-associated adverse events.
Other Agents
Analgesics:
Methadone*
↓ Methadone Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Antiarrhythmics:
Amiodarone, disopyramide, lidocaine
Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Antibiotics:
Clarithromycin*
↓ Clarithromycin
↑ 14-OH clarithromycin
Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.
Rifabutin* ↑ Rifabutin Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.
Rifampin* ↓ Nevirapine Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Anticonvulsants:
Carbamazepine, clonazepam, ethosuximide
Plasma concentrations of nevirapine and the anticonvulsant may be decreased. Use with caution and monitor virologic response and levels of anticonvulsants.
Antifungals:
Fluconazole*
↑ Nevirapine Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events.
Ketoconazole* ↓ Ketoconazole Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.
Itraconazole ↓ Itraconazole Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug.
Antithrombotics:
Warfarin
Plasma concentrations may be increased. Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.
Calcium channel blockers:
Diltiazem, nifedipine, verapamil
Plasma concentrations may be decreased. Appropriate doses for these combinations have not been established.
Cancer chemotherapy:
Cyclophosphamide
Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Ergot alkaloids:
Ergotamine
Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Immunosuppressants:
Cyclosporine, tacrolimus, sirolimus
Plasma concentrations may be decreased. Appropriate doses for these combinations have not been established.
Motility agents:
Cisapride
Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Opiate agonists:
Fentanyl
Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Oral contraceptives:
Ethinyl estradiol and Norethindrone*
↓ Ethinyl estradiol
↓ Norethindrone
Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended.


Table name:
Interacting Drug Interaction
Theophylline Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin Monitor phenytoin level (7)
Methotrexate Monitor for methotrexate toxicity (7)
Cyclosporine May increase serum creatinine. Monitor serum creatinine (7)


Table name:
Table 4: Drugs Having Clinically Important Interactions with Amphetamines
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact Concomitant use of MAOIs and CNS stimulants can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure.
Intervention Do not administer MAS-ER Capsules concomitantly or within 14 days after discontinuing MAOI [see CONTRAINDICATIONS (4) and WARNINGS AND PRECAUTIONS (5.6)].
Examples selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue
Serotonergic Drugs
Clinical Impact The concomitant use of MAS-ER Capsules and serotonergic drugs increases the risk of serotonin syndrome.
Intervention Initiate with lower doses and monitor patients for signs and symptoms of serotonin syndrome, particularly during MAS-ER Capsules initiation or dosage increase. If serotonin syndrome occurs, discontinue MAS-ER Capsules and the concomitant serotonergic drug(s) [see WARNINGS AND PRECAUTIONS (5.6)].
Examples selective serotonin reuptake inhibitors (SSRI), serotonin norepinephrine reuptake inhibitors (SNRI), triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John's Wort
CYP2D6 Inhibitors
Clinical Impact The concomitant use of MAS-ER Capsules and CYP2D6 inhibitors may increase the exposure of MAS-ER Capsules compared to the use of the drug alone and increase the risk of serotonin syndrome.
Intervention Initiate with lower doses and monitor patients for signs and symptoms of serotonin syndrome particularly during MAS-ER Capsules initiation and after a dosage increase. If serotonin syndrome occurs, discontinue MAS-ER Capsules and the CYP2D6 inhibitor [see WARNINGS AND PRECAUTIONS (5.6) and OVERDOSAGE (10)].
Examples paroxetine and fluoxetine (also serotonergic drugs), quinidine, ritonavir
Alkalinizing Agents
Clinical Impact Increase blood levels and potentiate the action of amphetamine.
Intervention Co-administration of MAS-ER Capsules and gastrointestinal or urinary alkalinizing agents should be avoided.
Examples Gastrointestinal alkalinizing agents (e.g., sodium bicarbonate). Urinary alkalinizing agents (e.g. acetazolamide, some thiazides).
Acidifying Agents
Clinical Impact Lower blood levels and efficacy of amphetamines.
Intervention Increase dose based on clinical response.
Examples Gastrointestinal acidifying agents (e.g., guanethidine, reserpine, glutamic acid HCl, ascorbic acid). Urinary acidifying agents (e.g., ammonium chloride, sodium acid phosphate, methenamine salts).
Tricyclic Antidepressants
Clinical Impact May enhance the activity of tricyclic or sympathomimetic agents causing striking and sustained increases in the concentration of d-amphetamine in the brain; cardiovascular effects can be potentiated.
Intervention Monitor frequently and adjust or use alternative therapy based on clinical response.
Examples desipramine, protriptyline
Proton Pump Inhibitors
Clinical Impact Time to maximum concentration (Tmax) of amphetamine is decreased compared to when administered alone.
Intervention Monitor patients for changes in clinical effect and adjust therapy based on clinical response.
Examples omeprazole


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
 Concomitant Drug  Effect on Concentration of Lamotrigine or Concomitant Drug  Clinical Comment
 Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel  ↓ Lamotrigine  Decreased Lamotrigine levels approximately 50%.
 ↓ levonorgestrel  Decrease in levonorgestrel component by 19%.
 Carbamazepine (CBZ) and CBZ epoxide  ↓ Lamotrigine  Addition of carbamazepine decreases Lamotrigine concentration approximately 40%.
 ? CBZ epoxide  May increase CBZ epoxide levels.
 Phenobarbital/Primidone  ↓ Lamotrigine  Decreased Lamotrigine concentration approximately 40%.
 Phenytoin (PHT)  ↓ Lamotrigine  Decreased Lamotrigine concentration approximately 40%.
 Rifampin  ↓ Lamotrigine  Decreased Lamotrigine AUC approximately 40%.
 Valproate  ↑ Lamotrigine  Increased Lamotrigine concentrations slightly more than 2-fold.
 ? valproate  Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
Table 2: Clinically Significant Drug Interactions with OPANA Injection
Benzodiazepines and other Central Nervous System (CNS) Depressants
Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death.
Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.4)].
Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue OPANA injection if serotonin syndrome is suspected.
Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)]. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
Intervention: The use of OPANA injection is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples: phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact: May reduce the analgesic effect of OPANA injection and/or precipitate withdrawal symptoms.
Intervention: Avoid concomitant use.
Examples: butorphanol, nalbuphine, pentazocine, buprenorphine,
Muscle Relaxants
Clinical Impact: Oxymorphone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of OPANA ER and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when OPANA is used concomitantly with anticholinergic drugs.
Anticholinergic Drugs
Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when OPANA injection is used concomitantly with anticholinergic drugs.
Cimetidine
Clinical Impact: Cimetidine can potentiate opioid-induced respiratory depression.
Intervention: Monitor patients for respiratory depression when OPANA ER and cimetidine are used concurrently.
Propofol
Clinical Impact: Incidence of bradycardia was increased when oxymorphone was combined with propofol for induction of anesthesia
Intervention: Do not use concurrently with Propofol.


Table name:
Table 3: Clinically Significant Drug Interactions with Ibuprofen
Drugs That Interfere with Hemostasis
Clinical Impact: Ibuprofen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of ibuprofen and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of CALDOLOR with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].
Intervention: Concomitant use of CALDOLOR and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)].
CALDOLOR is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: During concomitant use of CALDOLOR and ACE-inhibitors, ARBs, or beta- blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of CALDOLOR and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated.  Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of CALDOLOR with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Digoxin
Clinical Impact: The concomitant use of ibuprofen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of CADOLOR and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of CALDOLOR and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of CALDOLOR and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of CALDOLOR and cyclosporine may increase cyclosporine's nephrotoxicity.
Intervention: During concomitant use of CALDOLOR and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of ibuprofen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention: The concomitant use of ibuprofen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of CALDOLOR and pemetrexed, may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of CALDOLOR and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.

NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.

In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir ) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Do not exceed 40 mg atorvastatin daily


Table name:
Effects on steady-state fexofenadine pharmacokinetics after 7 days of co-administration with fexofenadine hydrochloride 120 mg every 12 hours (two times the recommended twice daily dose) in healthy volunteers (n=24)
Concomitant Drug CmaxSS
(Peak plasma concentration)
AUCss(0–12h)
(Extent of systemic exposure)
Erythromycin
(500 mg every 8 hrs)
+82% +109%
Ketoconazole
(400 mg once daily)
+135% +164%


Table name:
Table 6: Effect of VYVANSE on Other Drugs
Concomitant Drug Name or Drug Class Clinical Rationale Clinical Recommendation
Monoamine Oxidase Inhibitors (MAOIs) Concomitant use of MAOIs and CNS stimulants can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure. Do not administer VYVANSE concomitantly or within 14 days after discontinuing MAOI treatment [see Contraindications (4)]


Table name:
Table 2 Rifabutin Interaction Studies
Coadministered drug Dosing regimen of coadministered drug Dosing regimen of rifabutin Study population (n) Effect on rifabutin Effect on coadministered drug Recommendation
↑ indicates increase; ↓ indicates decrease; ↔ indicates no significant change
QD- once daily; BID- twice daily; TID – thrice daily
ND - No Data
AUC - Area under the Concentration vs. Time Curve; Cmax - Maximum serum concentration
ANTIVIRALS
Amprenavir 1200 mg BID × 10 days 300 mg QD × 10 days Healthy male subjects (6) ↑ AUC by 193%,
↑ Cmax by 119%
Reduce rifabutin dose by at least 50%. Monitor closely for adverse reactions.
Delavirdine 400 mg TID 300 mg QD HIV-infected patients (7) ↑ AUC by 230%,
↑ Cmax by 128%
↓ AUC by 80%,
↓ Cmax by 75%,
↓ Cmin by 17%
CONTRAINDICATED
Didanosine 167 or 250 mg BID × 12 days 300 or 600 mg QD × 1 HIV-infected patients (11)
Fosamprenavir/ ritonavir 700 mg BID plus ritonavir 100 mg BID × 2 weeks 150 mg every other day × 2 weeks Healthy subjects (15) ↔ AUCcompared to rifabutin 300 mg QD alone
↓ Cmax by 15%
↑ AUC by 35%compared to historical control (fosamprenavir/ritonavir 700/100 mg BID),
↑ Cmax by 36%,
↑ Cmin by 36%,
Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with fosamprenavir/ritonavir combination.
Indinavir 800 mg TID × 10 days 300 mg QD × 10 days Healthy subjects (10) ↑ AUC by 173%,
↑ Cmax by 134%
↓ AUC by 34%,
↓ Cmax by 25%,
↓ Cmin by 39%
Reduce rifabutin dose by 50%, and increase indinavir dose from 800 mg to 1000 mg TID.
Lopinavir/ ritonavir 400/100 mg BID × 20 days 150 mg QD × 10 days Healthy subjects (14) ↑ AUC by 203% also taking zidovudine 500 mg QD
↓ Cmax by 112%
Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with lopinavir/ritonavir combination. Monitor closely for adverse reactions. Reduce rifabutin dosage further, as needed.
Saquinavir/ ritonavir 1000/100 mg BID × 14 or 22 days 150 mg every 3 days × 21–22 days Healthy subjects ↑ AUC by 53% compared to rifabutin 150 mg QD alone
↑ Cmax by 88% (n=11)
↓ AUC by 13%,
↓ Cmax by 15%,
        (n=19)
Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with saquinavir/ritonavir combination. Monitor closely for adverse reactions.
Ritonavir 500 mg BID × 10 days 150 mg QD × 16 days Healthy subjects (5) ↑ AUC by 300%,
↑ Cmax by 150%
ND Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with lopinavir/ritonavir combination. Monitor closely for adverse reactions. Reduce rifabutin dosage further, as needed.
Tipranavir/ ritonavir 500/200 BID × 15 doses 150 mg single dose Healthy subjects (20) ↑ AUC by 190%,
↑ Cmax by 70%
Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with tipranavir/ritonavir combination. Monitor closely for adverse reactions. Reduce rifabutin dosage further, as needed.
Nelfinavir 1250 mg BID × 7–8 days 150 mg QD × 8 days HIV-infected patients (11) ↑ AUC by 83%, compared to rifabutin 300 mg QD alone
↑ Cmax by 19%
Reduce rifabutin dose by 50% (to 150 mg QD) and increase the nelfinavir dose to 1250 mg BID
Zidovudine 100 or 200 mg q4h 300 or 450 mg QD HIV-infected patients (16) ↓ AUC by 32%,
↓ Cmax by 48%,
Because zidovudine levels remained within the therapeutic range during coadministration of rifabutin, dosage adjustments are not necessary.
ANTIFUNGALS
Fluconazole 200 mg QD × 2 weeks 300 mg QD × 2 weeks HIV-infected patients (12) ↑ AUC by 82%,
↑ Cmax by 88%
Monitor for rifabutin associated adverse events. Reduce rifabutin dose or suspend rifabutin use if toxicity is suspected.
Posaconazole 200 mg QD × 10 days 300 mg QD × 17 days Healthy subjects (8) ↑ AUC by 72%,
↑ Cmax by 31%
↓ AUC by 49%,
↓ Cmax by 43%
If co-administration of these two drugs cannot be avoided, patients should be monitored for adverse events associated with rifabutin administration, and lack of posaconazole efficacy.
Itraconazole 200 mg QD 300 mg QD HIV-Infected patients (6) data from a case report ↓ AUC by 70%,
↓ Cmax by 75%,
If co-administration of these two drugs cannot be avoided, patients should be monitored for adverse events associated with rifabutin administration, and lack of itraconazole efficacy. In a separate study, one case of uveitis was associated with increased serum rifabutin levels following co-administration of rifabutin (300 mg QD) with itraconazole (600–900 mg QD).
Voriconazole 400 mg BID × 7 days (maintenance dose) 300 mg QD × 7 days Healthy male subjects (12) ↑ AUC by 331%,
↑ Cmax by 195%
↑ AUC by ~100%,
↑ Cmax by ~100%compared to voriconazole 200 mg BID alone
CONTRAINDICATED
ANTI-PCP (Pneumocystis carinii pneumonia)
Dapsone 50 mg QD 300 mg QD HIV-infected patients (16) ND ↓ AUC by 27 –40%
Sulfamethoxazole-Trimethoprim 800/160 mg 300 mg QD HIV-infected patients (12) ↓ AUC by 15–20%
ANTI-MAC (Mycobacterium avium intracellulare complex)
Azithromycin 500 mg QD × 1 day, then 250 mg QD × 9 days 300 mg QD Healthy subjects (6)
Clarithromycin 500 mg BID 300 mg QD HIV-infected patients (12) ↑ AUC by 75% ↓ AUC by 50% Monitor for rifabutin associated adverse events. Reduce dose or suspend use of rifabutin if toxicity is suspected. Alternative treatment for clarithromycin should be considered when treating patients receiving rifabutin
ANTI-TB (Tuberculosis)
Ethambutol 1200 mg 300 mg QD × 7 days Healthy subjects (10) ND
Isoniazid 300 mg 300 mg QD × 7 days Healthy subjects (6) ND
OTHER
Methadone 20 – 100 mg QD 300 mg QD × 13 days HIV-infected patients (24) ND
Ethinylestradiol (EE)/ Norethindrone (NE) 35 mg EE / 1 mg NE × 21 days 300 mg QD × 10 days Healthy female subjects (22) ND EE: ↓ AUC by 35%, ↓ Cmax by 20%
NE: ↓ AUC by 46%
Patients should be advised to use additional or alternative methods of contraception.
Theophylline 5 mg/kg 300 mg × 14 days Healthy subjects (11) ND


Table name: For patients with CLCR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients with CLCR <30 mL/min the dose of clarithromycin should be reduced by 75%.
Table 7. Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction
Concomitant Drug Class: Drug Name Effect on Concentration of Delavirdine or Concomitant Drug Clinical Comment
HIV-Antiviral Agents: Nucleoside Reverse Transcriptase Inhibitor
Didanosinea ↓Delavirdine ↓Didanosine Administration of didanosine (buffered tablets) and RESCRIPTOR should be separated by at least 1 hour.
HIV-Antiviral Agents: Non-nucleoside Reverse Transcriptase Inhibitors
NNRTI ↔Delavirdine ↑NNRTI Combining NNRTIs has not been shown to be beneficial. RESCRIPTOR should not be coadministered with another NNRTI.
HIV-Antiviral Agents: Protease Inhibitors
Indinavira ↑Indinavir A dose reduction of indinavir to 600 mg 3 times daily should be considered when RESCRIPTOR and indinavir are coadministered.
Lopinavir/Ritonavir ↑Lopinavir ↑Ritonavir Appropriate doses of this combination with respect to safety, efficacy, and pharmacokinetics have not been established.
Nelfinavira ↑Nelfinavir ↓Delavirdine Appropriate doses of this combination with respect to safety, efficacy, and pharmacokinetics have not been established (see CLINICAL PHARMACOLOGY: Tables 1 and 2).
Ritonavir ↑Ritonavir Appropriate doses of this combination with respect to safety, efficacy, and pharmacokinetics have not been established.
Saquinavira ↑Saquinavir A dose reduction of saquinavir (soft gelatin capsules) may be considered when RESCRIPTOR and saquinavir are coadministered (see CLINICAL PHARMACOLOGY: Table 1). Appropriate doses with respect to safety, efficacy, and pharmacokinetics have not been established.
HIV-Antiviral Agents: CCR5 Inhibitor
Maraviroc ↑Maraviroc Concomitant use of RESCRIPTOR and maraviroc has not been studied. However, RESCRIPTOR is a potent CYP3A4 inhibitor and the maraviroc dose should be reduced during coadministration. Refer to the full prescribing information for maraviroc (SELZENTRY) for dosing recommendations.
Other Agents
Acid blockers: Antacidsa ↓Delavirdine Doses of an antacid and RESCRIPTOR should be separated by at least 1 hour, because the absorption of delavirdine is reduced when coadministered with antacids.
Histamine H2-receptor antagonists: Cimetidine, famotidine, nizatidine, ranitidine ↓Delavirdine These agents increase gastric pH and may reduce the absorption of delavirdine. Although the effect of these drugs on delavirdine absorption has not been evaluated, chronic use of these drugs with RESCRIPTOR is not recommended.
Proton pump inhibitors: Omeprazole, lansoprazole ↓Delavirdine These agents increase gastric pH and may reduce the absorption of delavirdine. Although the effect of these drugs on delavirdine absorption has not been evaluated, chronic use of these drugs with RESCRIPTOR is not recommended.
Amphetamines ↑Amphetamines Use with caution.
Antidepressant: Trazodone ↑Trazodone Concomitant use of trazodone and RESCRIPTOR may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as RESCRIPTOR, the combination should be used with caution and a lower dose of trazodone should be considered.
Antiarrhythmics: Bepridil ↑Antiarrhythmics Use with caution. Increased bepridil exposure may be associated with life‑threatening reactions such as cardiac arrhythmias.
Amiodarone, lidocaine (systemic), quinidine, flecainide, propafenone Caution is warranted and therapeutic concentration monitoring is recommended, if available, for antiarrhythmics when coadministered with RESCRIPTOR.
Anticoagulant: Warfarin ↑Warfarin It is recommended that INR (international normalized ratio) be monitored.
Anti-infective: Clarithromycina ↑Clarithromycin When coadministered with RESCRIPTOR, clarithromycin should be adjusted in patients with impaired renal function:
Calcium channel blockers: Amlodipine, diltiazem, felodipine, isradipine, nifedipine, nicardipine, nimodipine, nisoldipine, verapamil ↑Calcium channel blockers Caution is warranted and clinical monitoring of patients is recommended.
Corticosteroid: Dexamethasone ↓Delavirdine Use with caution. RESCRIPTOR may be less effective due to decreased delavirdine plasma concentrations in patients taking these agents concomitantly.
Erectile dysfunction agents: Sildenafil ↑Sildenafil Sildenafil should not exceed a maximum single dose of 25 mg in a 48‑hour period.
HMG-CoA reductase inhibitors: Atorvastatin, cerivastatin, fluvastatin ↑Atorvastatin ↑Cerivastatin ↑Fluvastatin Use lowest possible dose of atorvastatin or cerivastatin, or fluvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin in combination with RESCRIPTOR.
Immunosuppressants: Cyclosporine, tacrolimus, rapamycin ↑Immunosuppressants Therapeutic concentration monitoring is recommended for immunosuppressant agents when coadministered with RESCRIPTOR.
Inhaled/nasal steroid: Fluticasone ↑Fluticasone Concomitant use of fluticasone and RESCRIPTOR may increase plasma concentrations of fluticasone. Use with caution. Consider alternatives to fluticasone, particularly for long-term use.
Narcotic analgesic: Methadone ↑Methadone Dosage of methadone may need to be decreased when coadministered with RESCRIPTOR.
Oral contraceptives: Ethinyl estradiol ↑Ethinyl estradiol Concentrations of ethinyl estradiol may increase. However, the clinical significance is unknown.


Table name:
AED Dosage of AED (mg/day) Dosage of POTIGA (mg/day) Influence of POTIGA on AED Influence of AED on POTIGA Dosage Adjustment
Carbamazepinea,b 600-2,400 300-1,200 None 31% decrease in AUC, 23% decrease in Cmax consider an increase in dosage of POTIGA when adding carbamazepinec
Phenytoina,b 120-600 300-1,200 None 34% decrease in AUC, 18% decrease in Cmax consider an increase in dosage of POTIGA when adding phenytoinc


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor
(boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
  Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
 Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine Decreased lamotrigine concentrations approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? carbamazepine epoxide May increase carbamazepine epoxide levels.
Lopinavir/ritonavir ↓ lamotrigine Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir ↓ lamotrigine Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine Increased lamotrigine concentrations slightly more than 2-fold.
? valproate There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.


Table name:
Table 3: Summary of AED Interactions with Oxcarbazepine
AED Coadministered Dose of AED
(mg/day)
Oxcarbazepine Dose
(mg/day)
Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval) Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine 400-2000 900 ncnc denotes a mean change of less than 10% 40% decrease [CI:17% decrease, 57% decrease]
Phenobarbital 100-150 600-1800 14% increase
[CI: 2% increase, 24% increase]
25% decrease
[CI:12% decrease, 51% decrease]
Phenytoin 250-500 600-1800
>1200-2400
nc , Pediatrics
up to 40% increaseMean increase in adults at high Oxcarbazepine doses
[CI: 12% increase, 60% increase]
30% decrease
[CI: 3% decrease, 48% decrease]
Valproic acid 400-2800 600-1800 nc 18% decrease
[CI:13% decrease, 40% decrease]


Table name:
Factors
Dosage Adjustment of Aripiprazole tablets
Known CYP2D6 Poor Metabolizers
Administer half of usual dose
KnownCYP2D6Poor Metabolizersand strongCYP3A4 inhibitors
Administer a quarter of usualdose
StrongCYP2D6 or CYP3A4inhibitors
Administerhalf of usual dose
StrongCYP2D6andCYP3A4 inhibitors
Administer a quarter of usualdose
StrongCYP3A4inducers
Double usual doseover 1 to 2 weeks


Table name:
Interacting  Drug
Interaction
Multivalent cation-containing products including 
antacids, metal cations or didanosine
Absorption of levofloxacin is decreased when  the tablet is taken within 2 hours of these products. (2.4, 7.1)
Warfarin
Effect may be enhanced. Monitor prothrombin time,  INR, watch for bleeding (7.2)
Antidiabetic agents
Carefully monitor blood glucose (5.12, 7.3)


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
 Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)  Avoid atorvastatin
 HIV protease inhibitor (lopinavir plus ritonavir)  Use with caution and lowest dose necessary
 Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)  Do not exceed 20 mg atorvastatin daily
 HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
 Do not exceed 40 mg atorvastatin daily


Table name:
Table 1: Clinically Significant Drug Interactions with Naproxen
Drugs That Interfere with Hemostasis
Clinical Impact: Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of naproxen tablets with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: Concomitant use of naproxen tablets and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen tablets are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: During concomitant use of naproxen tablets and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of naproxen tablets and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention During concomitant use of naproxen tablets with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact: The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of naproxen tablets and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen tablets and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of naproxen tablets and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of naproxen tablets and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of naproxen tablets and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of naproxen tablets and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of naproxen tablets and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact: Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention: Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen tablets are not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen tablets are not recommended.
Cholestyramine
Clinical Impact: Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention: Concomitant administration of cholestyramine with naproxen tablets are not recommended.
Probenecid
Clinical Impact: Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention: Patients simultaneously receiving naproxen tablets and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact: Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention: Patients simultaneously receiving naproxen tablets and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.


Table name:
Table 6: Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology (12.3)]
** Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg q12h voriconazole to healthy subjects
** Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects
*** Non-Nucleoside Reverse Transcriptase Inhibitors
Drug/Drug Class
(Mechanism of Interaction by the Drug)
Voriconazole Plasma Exposure
(Cmax and AUC τ after 200 mg q12h)
Recommendations for Voriconazole Dosage Adjustment/Comments
Rifampin* and Rifabutin*
(CYP450 Induction)
Significantly Reduced
Contraindicated
Efavirenz (400 mg q24h)**
(CYP450 Induction)
 
Efavirenz (300 mg q24h)**
(CYP450 Induction)
 
Significantly Reduced
 
 
Slight Decrease in  AUC τ
Contraindicated
 
 
When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)** (CYP450 Induction)
 
Low-dose Ritonavir (100 mg q12h)** (CYP450 Induction)
Significantly Reduced
 
 
Reduced
Contraindicated
 

Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Carbamazepine
(CYP450 Induction)
Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction
Contraindicated
Long Acting Barbiturates
(CYP450 Induction)
Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction
Contraindicated
Phenytoin*
(CYP450 Induction)
Significantly Reduced
Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg)
St. John’s Wort
(CYP450 inducer; P-gp inducer)
Significantly Reduced
Contraindicated
Oral Contraceptives** containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)
Increased
Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole** (CYP2C9, CYP2C19 and CYP3A4 Inhibition)
Significantly Increased
Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)
In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure
 
In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)
No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir
 
Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
 
Other NNRTIs***
(CYP3A4 Inhibition or CYP450 Induction)
In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure)
 
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure)
 
Frequent monitoring for adverse events and toxicity related to voriconazole
 
 
 
 
Careful assessment of voriconazole  effectiveness
 


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.5, 5.1, 7.1, 7.2, 7.3, 7.4)
Interacting Agents Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone Avoid simvastatin
Gemfibrozil, cyclosporine, danazol Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil Do not exceed 20 mg simvastatin daily
Grapefruit juice Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Interacting Drug
Interaction
Multivalent cation-containing products including antacids,
metal cations or didanosine
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin
Effect may be enhanced. Monitor prothrombin
time, INR, watch for bleeding (7.2)
Antidiabetic agents
Carefully monitor blood glucose (5.12, 7.3)


Table name:
Interacting Drug Interaction
Theophylline Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin Monitor phenytoin level (7)
Methotrexate Monitor for methotrexate toxicity (7)
Cyclosporine May increase serum creatinine. Monitor serum creatinine (7)


Table name:
Table 3 Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology ( 12.3), Table 4 for Magnitude of Interaction.
*The interaction between Nevirapine and the drug was evaluated in a clinical study. All other drug interactions shown are predicted.
 
Drug Name Effect on Concentration of Nevirapine or Concomitant Drug Clinical Comment
HIV Antiviral Agents: Protease Inhibitors (PIs)
Atazanavir/Ritonavir* ↓ Atazanavir
↑ Nevirapine
Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures.
Fosamprenavir*

Fosamprenavir/Ritonavir*
↓ Amprenavir
↑ Nevirapine

↓ Amprenavir
↑ Nevirapine
Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.
No dosing adjustments are required when nevirapine is coadministered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied.
Indinavir* ↓ Indinavir The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established.
Lopinavir/Ritonavir* ↓ Lopinavir Dosing in adult patients:
A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.
Dosing in pediatric patients:
Please refer to the Kaletra® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.
Nelfinavir* ↓ Nelfinavir M8
Metabolite
↓ Nelfinavir C min
The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established.
Saquinavir/Ritonavir The interaction between Nevirapine and saquinavir/ritonavir has not been evaluated The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz*
Delavirdine
Etravirine
Rilpivirine
↓ Efavirenz The appropriate doses of these combinations with respect to safety and efficacy have not been established.
Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial.
Hepatitis C Antiviral Agents
Boceprevir Plasma concentrations of boceprevir may be decreased due to induction of CYP3A4/5 by nevirapine. Nevirapine and boceprevir should not be coadministered because decreases in boceprevir plasma concentrations may result in a reduction in efficacy.
Telaprevir Plasma concentrations of telaprevir may be decreased due to induction of CYP3A4 by nevirapine and plasma concentrations of nevirapine may be increased due to inhibition of CYP3A4 by telaprevir. Nevirapine and telaprevir should not be coadministered because changes in plasma concentrations of nevirapine, telaprevir, or both may result in a reduction in telaprevir efficacy or an increase in nevirapine-associated adverse events.
Other Agents
Analgesics:
Methadone*
↓ Methadone Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadonemaintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Antiarrhythmics:
Amiodarone, disopyramide, lidocaine
Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Antibiotics:
Clarithromycin*

Rifabutin*

Rifampin*
↓ Clarithromycin
↑ 14-OH clarithromycin

↑ Rifabutin

↓ Nevirapine
Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.
Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.
Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients coinfected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Anticonvulsants:
Carbamazepine, clonazepam, ethosuximide
Plasma concentrations of nevirapine and the anticonvulsant may be decreased. Use with caution and monitor virologic response and levels of anticonvulsants.
Antifungals:
Fluconazole*

Ketoconazole*

Itraconazole
↑ Nevirapine


↓ Ketoconazole

↓ Itraconazole
Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events.
Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.
Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug.
Antithrombotics:
Warfarin
Plasma concentrations may be increased. Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.
Calcium channel blockers:
Diltiazem, nifedipine, verapamil
Plasma concentrations may be decreased. Appropriate doses for these combinations have not been established.
Cancer chemotherapy:
Cyclophosphamide
Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Ergot alkaloids:
Ergotamine
Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Immunosuppressants:

Cyclosporine, tacrolimus, sirolimus
Plasma concentrations may be decreased. Appropriate doses for these combinations have not been established.
Motility agents:
Cisapride
Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Opiate agonists:
Fentanyl
Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Oral contraceptives:
Ethinyl estradiol and
Norethindrone*
↓Ethinyl estradiol
↓Norethindrone
Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.
albuterol, famotidine nizatidine
systemic and inhaled felodipine norfloxacin
amoxicillin finasteride ofloxacin
ampicillin, hydrocortisone omeprazole
with or without isoflurane prednisone, prednisolone
sulbactam isoniazid ranitidine
atenolol isradipine rifabutin
azithromycin influenza vaccine roxithromycin
caffeine, ketoconazole sorbitol
  dietary ingestion lomefloxacin (purgative doses do not
cefaclor mebendazole inhibit theophylline
co-trimoxazole medroxyprogesterone absorption)
(trimethoprim and methylprednisolone sucralfate
sulfamethoxazole) metronidazole terbutaline, systemic
diltiazem metoprolol terfenadine
dirithromycin nadolol tetracycline
enflurane nifedipine tocainide


Table name:
Interacting Agents Prescribing Recommendations 
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone Avoid simvastatin 
Gemfibrozil, cyclosporine,danazol  Do not exceed 10 mg simvastatindaily 
Amiodarone, verapamil Do not exceed 20 mg simvastatin daily 
Diltiazem Do not exceed 40 mg simvastatin daily
Grapefruit juice Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Drugs that Affect Renal Function A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDS], COX-2 inhibitors may impair the excretion of digoxin.
Antiarrhythmics Dofetilide Concomitant administration with digoxin was associated with a higher rate of torsades de pointes.
  Sotalol Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
  Dronedarone Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone Analog Teriparatide Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement Thyroid Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics Epinephrine
Norepinephrine
Dopamine
Can increase the risk of cardiac arrhythmias
Neuromuscular Blocking Agents Succinylcholine May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.
Supplements Calcium If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers   Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.


Table name:
Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
* Change relative to reference
Coadministered Drug
Dosing Schedule
Effect on Active
Moiety (Risperidone + 9-
Hydroxy- Risperidone (Ratio*)
Risperidone Dose
Recommendation

Coadministered Drug
Risperidone
AUC
Cmax

Enzyme (CYP2D6)
Inhibitors





Fluoxetine
20 mg/day 
2 or 3 mg twice
daily
1.4 
1.5
Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine
10 mg/day 
4 mg/day
1.3
-
Re-evaluate dosing. 

20 mg/day 
4 mg/day
1.6
-
Do not exceed 8 mg/day

40 mg/day 
4 mg/day
1.8
-

Enzyme (CYP3A/ PgP inducers) Inducers





Carbamazepine 
573 ± 168 mg/day
3 mg twice daily
0.51 
0.55
Titrate dose upwards.
Do not exceed twice the patient’s usual dose
Enzyme (CYP3A)
Inhibitors





Ranitidine 
150 mg twice daily
1 mg single dose
1.2 
1.4
Dose adjustment not
needed
Cimetidine 
400 mg twice daily
1 mg single dose
1.1 
1.3
Dose adjustment not
needed
Erythromycin 

500 mg four times
daily
1 mg single dose
1.1 
0.94
Dose adjustment not
needed






Other Drugs





Amitriptyline 
50 mg twice daily
3 mg twice daily
1.2 
1.1
Dose adjustment not
needed


Table name:
Interacting  Agents 
Prescribing  Recommendations 
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, 
posaconazole, voriconazole, erythromycin, clarithromycin, 
telithromycin, HIV protease inhibitors, boceprevir, telaprevir, 
nefazodone, cobicistatcontaining products), gemfibrozil, 
cyclosporine, danazol 
 Contraindicated with simvastatin 
Verapamil, diltiazem, dronedarone
Do not exceed 10 mg simvastatin daily 
Amiodarone, amlodipine, ranolazine
Do not exceed 20 mg simvastatin daily 
Lomitapide
For patients with HoFH, do not exceed 
20 mg simvastatin dailyFor patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice 
Avoid grapefruit juice  


Table name:
Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s) Recommendation Comments
Tizanidine Contraindicated Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)].
Theophylline Avoid Use (Plasma Exposure Likely to be Increased and Prolonged) Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions (5.6).]
Drugs Known to Prolong QT Interval Avoid Use Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.10) and Use in Specific Populations (8.5)].
Oral antidiabetic drugs Use with caution Glucose-lowering effect potentiated Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported . Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs. [see Adverse Reactions (6.1).]
Phenytoin Use with caution Altered serum levels of phenytoin (increased and decreased) To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after coadministration of ciprofloxacin with phenytoin.
Cyclosporine Use with caution (transient elevations in serum creatinine) Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs Use with caution (Increase in anticoagulant effect) The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole Use with caution Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after coadministration with ciprofloxacin [see Warnings and Precautions (5.15)].
Clozapine Use with caution Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs Use with caution Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil Use with caution 2-fold increase in exposure Monitor for sildenafil toxicity (see Pharmacokinetics -(12.3)-] .
Duloxetine Avoid Use 5-fold increase in duloxetine exposure If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx ® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products) Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2)]. Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels) Potentiation of ciprofloxacin toxicity may occur.


Table name:
Interacting Drug
Interaction
Multivalent cation-containing products including antacids,
metal cations or didanosine
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin
Effect may be enhanced. Monitor prothrombin
time, INR, watch for bleeding (7.2)
Antidiabetic agents
Carefully monitor blood glucose (5.12, 7.3)


Table name:
Table 9: Drugs That are Affected by and Affecting Ciprofloxacin Tablets
Drugs That are Affected by C iprofloxacin   Tablets
Drug(s) Recommendation Comments
Tizanidine Contraindicated Concomitant administration of tizanidine and ciprofloxacin tablets is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications ( 4.2 )]
Theophylline Avoid Use (Plasma Exposure Likely to be Increased and Prolonged) Concurrent administration of ciprofloxacin tablets with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [s ee Warnings and Precautions ( 5.9 ) ] .
Drugs Known to Prolong QT Interval Avoid Use Ciprofloxacin tablets may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions ( 5.11 )   and Use in
Specific Populations ( 8.5 )].
Oral antidiabetic drugs Use with caution Glucose-lowering effect potentiated
Hypoglycemia sometimes severe has been reported when ciprofloxacin tablets and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin tablets is co-administered with oral antidiabetic drugs [see Adverse Reactions (6.1)].
Phenytoin Use with caution Altered serum levels of phenytoin (increased and decreased) To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin tablets discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin tablets with phenytoin.
Cyclosporine Use with caution (transient elevations in serum creatinine) Monitor renal function (in particular serum creatinine) when ciprofloxacin tablets is co-administered with cyclosporine.
Anti-coagulant drugs Use with caution (Increase in anticoagulant effect) The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin tablets to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin tablets with an oral anti-coagulant (for example, warfarin).
Methotrexate Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin tablets therapy is indicated.
Ropinirole Use with caution Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin tablets [see Warnings and Precautions ( 5.16 ) ] .
Clozapine Use with caution Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin tablets are advised.
NSAIDs Use with caution Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil Use with caution Two-fold increase in exposure Monitor for sildenafil toxicity [see clinical Pharmacology (12.3)].
Duloxetine Avoid Use
Five-fold increase in duloxetine exposure
If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life Ciprofloxacin tablets inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin Tablets
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx®
(didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)
Ciprofloxacin tablets should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration ( 2.4 ) ] .








Decrease ciprofloxacin tablets absorption, resulting in lower serum and urine levels
Probenecid
Use with caution (interferes with renal tubular secretion of ciprofloxacin tablets and increases ciprofloxacin tablets serum levels)
Potentiation of ciprofloxacin tablets toxicity may occur.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor
(boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Concomitant Drug Name or Drug Class
Clinical Rationale
Clinical Recommendation

StrongCYP3A4Inhibitors (e.g.,itraconazole,clarithromycin) or strongCYP2D6inhibitors (e.g.,quinidine,fluoxetine,paroxetine) 
The concomitant use of aripiprazole tablets withstrong CYP3A4 orCYP2D6inhibitorsincreasedthe exposure ofaripiprazole tabletscomparedto the use of aripiprazole tabletsalone [seeCLINICALPHARMACOLOGY( 12.3)].
Withconcomitant use of aripiprazole tablets with a strongCYP3A4inhibitororCYP2D6inhibitor, reducethearipiprazole tablets dosage [see DOSAGEANDADMINISTRATION( 2.7)].
StrongCYP3A4Inducers (e.g.,carbamazepine,rifampin)
The concomitant use of aripiprazole tabletsandcarbamazepine decreased the exposure of aripiprazole tablets compared to the use of aripiprazole tablets alone [see CLINICALPHARMACOLOGY( 12.3)].
Withconcomitant use of aripiprazole tablets with a strongCYP3A4inducer, consider increasing the aripiprazole tabletsdosage [see DOSAGE ANDADMINISTRATIO( 2.7)].
AntihypertensiveDrugs
Duetoitsalphaadrenergicantagonism,aripiprazole tablets hasthepotentialtoenhance the effect of certainantihypertensive agents.
Monitor bloodpressureand adjustdoseaccordingly [seeWARNINGS AND PRECAUTIONS( 5.7)].
Benzodiazepines(e.g., lorazepam)
Theintensityofsedationwas greaterwith the combination of oral aripiprazole tabletsandlorazepam as comparedtothat observedwith aripiprazole alone.Theorthostatichypotension observed wasgreaterwith the combination as comparedtothatobserved withlorazepamalone [seeWARNINGSANDPRECAUTIONS( 5.7)]
Monitorsedation and blood pressure.Adjust dose accordingly.


Table name: Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.During concomitant use of DYLOJECT and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of DYLOJECT and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6) ]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Table 2: Clinically Significant Drug Interactions with Diclofenac
Drugs That Interfere with Hemostasis
Clinical Impact:
Intervention: Monitor patients with concomitant use of DYLOJECT with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11) ].
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2) ].
Intervention: Concomitant use of DYLOJECT and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11) ]. DYLOJECT is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:
Intervention:
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of DYLOJECT with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6) ].
Digoxin
Clinical Impact: The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of DYLOJECT and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of DYLOJECT and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of DYLOJECT and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of DYLOJECT and cyclosporine may increase cyclosporine's nephrotoxicity.
Intervention: During concomitant use of DYLOJECT and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2) ].
Intervention: The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of DYLOJECT and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of DYLOJECT and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Inhibitors or Inducers of Cytochrome P450 2C9
Clinical Impact: Diclofenac is metabolized by cytochrome P450 enzymes, predominantly by CYP2C9. Co-administration of diclofenac with CYP2C9 inhibitors (e.g. voriconazole) may enhance the exposure and toxicity of diclofenac whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of diclofenac.
Intervention: Use caution when dosing diclofenac with CYP2C9 inhibitors or inducers, a dosage adjustment may be warranted [see Clinical Pharmacology (12.3) ].


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine Decreased lamotrigine concentrations approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? carbamazepine epoxide May increase carbamazepine epoxide levels.
Lopinavir/ritonavir ↓ lamotrigine Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir ↓ lamotrigine Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine Increased lamotrigine concentrations slightly more than 2 fold.
? valproate There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
 Factors
 Dosage Adjustments for Aripiprazole
 Known CYP2D6 Poor Metabolizers
 Administer half of usual dose
 Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors
 Administer a quarter of usual dose
 Strong CYP2D6 or CYP3A4 inhibitors
 Administer half of usual dose
 Strong CYP2D6 and CYP3A4 inhibitors
 Administer a quarter of usual dose
 Strong CYP3A4 inducers
 Double usual dose over 1 to 2 weeks


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
 Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration  Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
 Drugs that may alter T 4 and T 3 metabolism
 Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
AED Coadministered AED Concentration Topiramate Concentration
Phenytoin
NC or 25% increase Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
48% decrease


Carbamazepine (CBZ)
NC
40% decrease
CBZ epoxide Is not administered but is an active metabolite of carbamazepine.
NC
NE
Valproic acid
11% decrease
14% decrease
Phenobarbital
NC
NE
Primidone
NC
NE
Lamotrigine
NC at TPM doses up to 400 mg/day
13% decrease


Table name:
Laboratory Tests Effect of Salicylates
Thyroid Function Decreased PBI; increased T 3 uptake
Urinary Sugar False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5 g qd)
5 Hydroxyindole acetic acid False negative with fluorometric test
Acetone, Ketone Bodies False positive FeCl 3 in Gerhardt reaction; red color persists with boiling
17-OH corticosteroids False reduced values with >4.8 g qd salicylate
Vanilmandelic Acid False reduced values
Uric Acid May increase or decrease depending on dose
Prothrombin Decreased levels; slightly increased prothrombin time


Table name:
Drug Type of Interaction Effect**

Adenosine

Theophylline blocks adenosine receptors.

Higher doses of adenosine may be required to achieve desired effect.

Alcohol 

A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours.

30% increase 

Allopurinol 

Decreases theophylline clearance at allopurinol doses ≥600 mg/day.

25% increase 

Aminoglutethimide

Increases theophylline clearance by induction of microsomal enzyme activity.

25% decrease 

Carbamazepine

Similar to aminoglutethimide.

30% decrease

Cimetidine

Decreases theophylline clearance by inhibiting cytochrome P450 1A2.

70% increase

Ciprofloxacin

Similar to cimetidine.

40% increase

Clarithromycin

Similar to erythromycin.

25% increase

Diazepam  

Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. 

Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.

Disulfiram 

Decreases theophylline clearance by inhibiting hydroxylation and demethylation.

50% increase 

Enoxacin

Similar to cimetidine.

300% increase

Ephedrine

Synergistic CNS effects.

Increased frequency of nausea, nervousness, and insomnia.

Erythromycin 

 

Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3.

35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.

Estrogen 

Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown.

30% increase 

 

 

Flurazepam

Similar to diazepam.

Similar to diazepam.

Fluvoxamine

Similar to cimetidine.

Similar to cimetidine.

Halothane  

Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines.

Increased risk of ventricular arrhythmias. 

Interferon, human recombinant alpha-A

Decreases theophylline clearance.

100% increase 

Isoproterenol (IV)

Increases theophylline clearance.

20% decrease

Ketamine 

Pharmacologic. 

May lower theophylline seizure threshold

Lithium

Theophylline increases renal lithium clearance.

Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.

Lorazepam

Similar to diazepam.

Similar to diazepam.

Methotrexate (MTX)

Decreases theophylline clearance.

 

20% increase after low dose MTX, higher dose MTX may have a greater effect.

Mexiletine

Similar to disulfiram.

80% increase

Midazolam

Similar to diazepam.

Similar to diazepam.

Moricizine

Increases theophylline clearance.

25% decrease

Pancuronium 

Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition.

Larger dose of pancuronium may be required to achieve neuromuscular blockade.

Pentoxifylline

Decreases theophylline clearance.

 30% increase

Phenobarbital (PB) 

Similar to aminoglutethimide. 

25% decrease after two weeks of concurrent PB.

Phenytoin

Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption.

Serum theophylline and phenytoin concentrations decrease about 40%.

Propafenone 

Decreases theophylline clearance and pharmacologic interaction. 

40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.

Propranolol 

Similar to cimetidine and pharmacologic interaction. 

100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.

Rifampin 

Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity.

20-40% decrease 
St. John’sWort (Hypericum Perforatum) Decrease in theophylline plasma concentrations. Higher doses of theophylline may be required to achieve desired effect. Stopping St. John’s Wort may result in theophylline toxicity.

Sulfinpyrazone

Increase theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline.

20% decrease

Tacrine

Similar to cimetidine, also increases renal clearance of theophylline.

90% increase

Thiabendazole

Decreases theophylline clearance.

190% increase

Ticlopidine

Decreases theophylline clearance.

60% increase

Troleandomycin 

Similar to erythromycin. 

33-100% increase depending on troleandomycin dose.

Verapamil

Similar to disulfiram.

20% increase


Table name:
Interacting  Drug 
Interaction 
Multivalent cation-containing products including antacids, metal cations or didanosine 
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin 
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents 
Carefully monitor blood glucose (5.11, 7.3)


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine Do not exceed 10 mg atorvastatin daily
Clarithromycin, itraconazole, HIV protease inhibitors (ritonavir plus saquinavir or lopinavir plus ritonavir) Caution when exceeding doses > 20 mg atorvastatin daily. The lowest dose necessary should be used.


Table name:
Summary of AED interactions with topiramate ( 7.1).
AED Co-administered AED Concentration Topiramate Concentration
Phenytoin NC or 25% increase a 48% decrease
Carbamazepine (CBZ) NC 40% decrease
CBZ epoxide b NC NE
Valproic acid 11% decrease 14% decrease
Phenobarbital NC NE
Primidone NC NE
Lamotrigine NC at TPM doses up to 400mg/day 13% decrease


Table name:
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitors (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Concomitant Drug Name or Drug Class
Clinical Rationale
Clinical Recommendation

StrongCYP3A4Inhibitors (e.g.,itraconazole,clarithromycin) or strongCYP2D6inhibitors (e.g.,quinidine,fluoxetine,paroxetine) 
The concomitant use of aripiprazole tablets withstrong CYP3A4 orCYP2D6inhibitorsincreasedthe exposure ofaripiprazole tabletscomparedto the use of aripiprazole tabletsalone[seeCLINICALPHARMACOLOGY(12.3)].
Withconcomitant use of aripiprazole tablets with a strongCYP3A4inhibitororCYP2D6inhibitor, reducethearipiprazole tablets dosage[see DOSAGEANDADMINISTRATION(2.7)].
StrongCYP3A4Inducers (e.g.,carbamazepine,rifampin)
The concomitant use of aripiprazole tabletsandcarbamazepine decreased the exposure of aripiprazole tablets compared to the use of aripiprazole tablets alone [see CLINICALPHARMACOLOGY(12.3)].
Withconcomitant use of aripiprazole tablets with a strongCYP3A4inducer, consider increasing the aripiprazole tabletsdosage[see DOSAGE ANDADMINISTRATIO(2.7)].
AntihypertensiveDrugs
Duetoitsalphaadrenergicantagonism,aripiprazole tablets hasthepotentialtoenhance the effect of certainantihypertensive agents.
Monitor bloodpressureand adjustdoseaccordingly[seeWARNINGS AND PRECAUTIONS(5.7)].
Benzodiazepines(e.g., lorazepam)
Theintensityofsedationwas greaterwith the combination of oral aripiprazole tabletsandlorazepam as comparedtothat observedwith aripiprazole alone.Theorthostatichypotension observed wasgreaterwith the combination as comparedtothatobserved withlorazepamalone[seeWARNINGSANDPRECAUTIONS(5.7)]
Monitorsedation and blood pressure.Adjust dose accordingly.


Table name:
Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol, famotidine nizatidine
systemic and inhaled felodipine norfloxacin
amoxicillin finasteride ofloxacin
ampicillin, hydrocortisone omeprazole
with or without isoflurane prednisone, prednisolone
sulbactam isoniazid ranitidine
atenolol isradipine rifabutin
azithromycin influenza vaccine roxithromycin
caffeine, ketoconazole sorbitol
  dietary ingestion lomefloxacin (purgative doses do not
cefaclor mebendazole inhibit theophylline
co-trimoxazole medroxyprogesterone absorption)
(trimethoprim and methylprednisolone sucralfate
sulfamethoxazole) metronidazole terbutaline, systemic
diltiazem metoprolol terfenadine
dirithromycin nadolol tetracycline
enflurane nifedipine tocainide


Table name:
Calcium Channel Blockers Antifungals Antibiotics Glucocorticoids Other Drugs
diltiazem fluconazole azithromycin methylprednisolone allopurinol
nicardipine itraconazole clarithromycin   amiodarone
verapamil ketoconazole erythromycin   bromocriptine
  voriconazole quinupristin/   colchicine
    dalfopristin   danazol
        imatinib
        metoclopramide
        nefazodone
        oral contraceptives


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C Protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Table 5: Established Drug Interactions Based on Studies with Didanosine or Studies with Buffered Formulations of Didanosine and Expected to Occur with Didanosine
↑Indicates increase.
↓Indicates decrease.
Drug Effect Clinical Comment
ganciclovir ↑didanosine concentration If there is no suitable alternative to ganciclovir, then use in combination with didanosine with caution. Monitor for didanosine-associated toxicity.
methadone ↓didanosine concentration If coadministration of methadone and didanosine is necessary, the recommended formulation of didanosine is didanosine delayed-release capsules. Patients should be closely monitored for adequate clinical response when didanosine is coadministered with methadone, including monitoring for changes in HIV RNA viral load. Do not coadminister methadone with didanosine pediatric powder due to significant decreases in didanosine concentrations.
nelfinavir No interaction 1 hour after didanosine Administer nelfinavir 1 hour after didanosine.
tenofovir disoproxil fumarate ↑didanosine concentration A dose reduction of didanosine to the following dosage once daily taken together with tenofovir disoproxil fumarate and a light meal (400 kcalories or less and 20% fat or less ) or in the fasted state is recommended.Coadministration of didanosine with food decreases didanosine concentrations. Thus, although not studied, it is possible that coadministration with heavier meals could reduce didanosine concentrations further. 250 mg (adults weighing at least 60 kg with creatinine clearance of at least 60 mL/min) 200 mg (adults weighing less than 60 kg with creatinine clearance of at least 60 mL/min) Patients should be monitored for didanosine-associated toxicities and clinical response.


Table name:
Table 18. Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug Dosing Schedule Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone Ratio Change relative to reference ) Risperidone Dose Recommendation
Coadministered Drug Risperidone AUC Cmax
Enzyme (CYP2D6) Inhibitors
Fluoxetine 20 mg/day 2 mg or
3 mg twice daily
1.4 1.5 Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine 10 mg/day 4 mg/day 1.3 -- Re-evaluate dosing. Do not exceed 8 mg/day
20 mg/day 4 mg/day 1.6 --
40 mg/day 4 mg/day 1.8 --
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine 573 mg/day ± 168 mg/day 3 mg twice daily 0.51 0.55 Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine 150 mg twice daily 1 mg single dose 1.2 1.4 Dose adjustment not needed
Cimetidine 400 mg twice daily 1 mg single dose 1.1 1.3 Dose adjustment not needed
Erythromycin 500 mg four times daily 1 mg single dose 1.1 0.94 Dose adjustment not needed
Other Drugs
Amitriptyline 50 mg twice daily 3 mg twice daily 1.2 1.1 Dose adjustment not needed


Table name:
Table 5: Drug Interactions that Result in Increased Concentrations of the Concomitant Drug
Drug Class or Drug Name Clinical Recommendations
Digoxin (P-gp substrate) Measure serum digoxin concentrations before initiating CERDELGA. Reduce digoxin dose by 30% and continue monitoring.
Other P-gp substrates
(e.g., phenytoin, colchicine, dabigatran etexilate)
Monitor therapeutic drug concentrations, as indicated, or consider reducing the dosage of the concomitant drug and titrate to clinical effect.
CYP2D6 substrates Metoprolol; tricyclic antidepressants (e.g., nortriptyline, amitriptyline, imipramine); phenothiazines (e.g., perphenazine, chloropromazine).


Table name:
CONCOMITANT DRUG CLINICAL EFFECT(S)
Amphetamines, cocaine, other sympathomimetic agents Additive hypertension, tachycardia, possibly cardiotoxicity
Atropine, scopolamine, antihistamines, other anticholinergic agents Additive or super-additive tachycardia, drowsiness
Amitriptyline, amoxapine, desipramine, other tricyclic antidepressants Additive tachycardia, hypertension, drowsiness
Barbiturates, benzodiazepines, ethanol, lithium, opioids, buspirone, antihistamines, muscle relaxants, other CNS depressants Additive drowsiness and CNS depression
Disulfiram A reversible hypomanic reaction was reported in a 28 y/o man who smoked marijuana; confirmed by dechallenge and rechallenge
Fluoxetine A 21 y/o female with depression and bulimia receiving 20 mg/day fluoxetine × 4 wks became hypomanic after smoking marijuana; symptoms resolved after 4 days
Antipyrine, barbiturates Decreased clearance of these agents, presumably via competitive inhibition of metabolism
Theophylline Increased theophylline metabolism reported with smoking of marijuana; effect similar to that following smoking tobacco


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine ↓ levonorgestrel Decreased lamotrigine concentrations approximately 50% Decrease in levonorgestrel component by 19%
Carbamazepine and carbamazepine epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%
? carbamazepine epoxide May increase CBZ epoxide levels
Lopinavir/ritonavir ↓ lamotrigine Decreased lamotrigine concentration approximately 50%
Atazanavir/ritonavir ↓ lamotrigine Decreased lamotrigine AUC approximately 32%
Phenobarbital/Primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%
Phenytoin ↓ lamotrigine Decreased lamotrigine concentration approximately 40%
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%
Valproate ↑lamotrigine Increased lamotrigine concentrations slightly more than 2-fold
? valproate There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.


Table name:
Table 2 Steady-State Plasma Concentrations of Felbamate When Coadministered With Other AEDs
AED Coadministered AED Concentration Felbamate Concentration
Phenytoin
Valproate No significant effect.
Carbamazepine (CBZ)
Not administered but an active metabolite of carbamazepine.CBZ epoxide

Phenobarbital


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
a = Plasma concenrtration increased 25% in some patients, generally those on a twice a day dosing regimen
of phenytoin.
b = Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated
AED Co-administered
AED Concentration
Topiramate Concentration
Phenytoin
NC or 25% increasea
48% decrease
Carbamazepine (CBZ)
NC
40% decrease
CBZ epoxideb
NC
NE
Valproic acid
11% decrease
14% decrease
Phenobarbital
NC
NE
Primidone
NC
NE
Lamotrigine
NC at TPM doses up to 400 mg/day
13% decrease


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( 7.2)
Antidiabetic agents Carefully monitor blood glucose ( 5.12, 7.3)


Table name:
 Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.11, 7.3)


Table name:
Table 2: Clinically Significant Drug Interactions with STARLIX
Drugs That May Increase the Blood-Glucose-Lowering Effect of STARLIX and Susceptibility to Hypoglycemia
Drugs: Nonsteroidal anti-inflammatory drugs (NSAIDs), salicylates, monoamine oxidase inhibitors, non-selective beta-adrenergic-blocking agents, anabolic hormones (e.g. methandrostenolone), guanethidine, gymnema sylvestre, glucomannan, thioctic acid, and inhibitors of CYP2C9 (e.g. amiodarone, fluconazole, voriconazole, sulfinpyrazone), alcohol.
Intervention: Dose reductions and increased frequency of glucose monitoring may be required when STARLIX is coadministered with these drugs.
Drugs and Herbals That May Reduce the Blood-Glucose-Lowering Effect of STARLIX and Increase Susceptibility to Hyperglycemia
Drugs: Thiazides, corticosteroids, thyroid products, sympathomimetics, somatropin, somatostatin analogues (e.g. lanreotide, octreotide), and CYP inducers (e.g. rifampin, phenytoin and St John’s Wort).
Intervention: Dose increases and increased frequency of glucose monitoring may be required when STARLIX is coadministered with these drugs.
Drugs That May Blunt Signs and Symptoms of Hypoglycemia
Drugs: beta-blockers, clonidine, guanethidine, and reserpine
Intervention: Increased frequency of glucose monitoring may be required when STARLIX is coadministered with these drugs.


Table name:
Table 4. Sevelamer Drug Interactions
Oral drugs for which sevelamer did not alter the pharmacokinetics when administered concomitantly
Digoxin
Enalapril
Iron
Metoprolol
Warfarin
Oral drugs that have demonstrated interaction with sevelamer and are to be dosed separately from Renvela
Dosing Recommendations
Ciprofloxacin
Mycophenolate mofetil
Take at least 2 hours before or 6 hours after sevelamer
Take at least 2 hours before sevelamer


Table name:
Table 3. Drugs That May Alter T4 and Triiodothyronine (T3) Serum Transport Without Affecting Free Thyroxine (FT4) Concentration (Euthyroidism)
Drug or Drug Class Effect
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
These drugs may increase serum thyroxine-binding globulin (TBG) concentration.
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
These drugs may decrease serum TBG concentration.
Potential impact (below): Administration of these agents with SYNTHROID results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations.
Salicylates (> 2 g/day) Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total T4 levels may decrease by as much as 30%.
Other drugs:
Carbamazepine
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non-Steroidal Anti-inflammatory Drugs
- Fenamates
These drugs may cause protein-binding site displacement. Furosemide has been shown to inhibit the protein binding of T4 to TBG and albumin, causing an increase free T4 fraction in serum. Furosemide competes for T4-binding sites on TBG, prealbumin, and albumin, so that a single high dose can acutely lower the total T4 level. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total and free T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. Closely monitor thyroid hormone parameters.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice Avoid grapefruit juice


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin dailyFor patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice Avoid grapefruit juice


Table name:
Drug Type of Interaction Effect**

Adenosine

Theophylline blocks adenosine receptors.

Higher doses of adenosine may be required to achieve desired effect.

Alcohol 

A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours.

30% increase 

Allopurinol 

Decreases theophylline clearance at allopurinol doses ≥600 mg/day.

25% increase 

Aminoglutethimide

Increases theophylline clearance by induction of microsomal enzyme activity.

25% decrease 

Carbamazepine

Similar to aminoglutethimide.

30% decrease

Cimetidine

Decreases theophylline clearance by inhibiting cytochrome P450 1A2.

70% increase

Ciprofloxacin

Similar to cimetidine.

40% increase

Clarithromycin

Similar to erythromycin.

25% increase

Diazepam  

Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. 

Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.

Disulfiram 

Decreases theophylline clearance by inhibiting hydroxylation and demethylation.

50% increase 

Enoxacin

Similar to cimetidine.

300% increase

Ephedrine

Synergistic CNS effects.

Increased frequency of nausea, nervousness, and insomnia.

Erythromycin 

 

Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3.

35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.

Estrogen 

Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown.

30% increase 

 

 

Flurazepam

Similar to diazepam.

Similar to diazepam.

Fluvoxamine

Similar to cimetidine.

Similar to cimetidine.

Halothane  

Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines.

Increased risk of ventricular arrhythmias. 

Interferon, human recombinant alpha-A

Decreases theophylline clearance.

100% increase 

Isoproterenol (IV)

Increases theophylline clearance.

20% decrease

Ketamine 

Pharmacologic. 

May lower theophylline seizure threshold

Lithium

Theophylline increases renal lithium clearance.

Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.

Lorazepam

Similar to diazepam.

Similar to diazepam.

Methotrexate (MTX)

Decreases theophylline clearance.

 

20% increase after low dose MTX, higher dose MTX may have a greater effect.

Mexiletine

Similar to disulfiram.

80% increase

Midazolam

Similar to diazepam.

Similar to diazepam.

Moricizine

Increases theophylline clearance.

25% decrease

Pancuronium 

Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition.

Larger dose of pancuronium may be required to achieve neuromuscular blockade.

Pentoxifylline

Decreases theophylline clearance.

 30% increase

Phenobarbital (PB) 

Similar to aminoglutethimide. 

25% decrease after two weeks of concurrent PB.

Phenytoin

Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption.

Serum theophylline and phenytoin concentrations decrease about 40%.

Propafenone 

Decreases theophylline clearance and pharmacologic interaction. 

40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.

Propranolol 

Similar to cimetidine and pharmacologic interaction. 

100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.

Rifampin 

Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity.

20-40% decrease 
St. John’sWort (Hypericum Perforatum) Decrease in theophylline plasma concentrations. Higher doses of theophylline may be required to achieve desired effect. Stopping St. John’s Wort may result in theophylline toxicity.

Sulfinpyrazone

Increase theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline.

20% decrease

Tacrine

Similar to cimetidine, also increases renal clearance of theophylline.

90% increase

Thiabendazole

Decreases theophylline clearance.

190% increase

Ticlopidine

Decreases theophylline clearance.

60% increase

Troleandomycin 

Similar to erythromycin. 

33-100% increase depending on troleandomycin dose.

Verapamil

Similar to disulfiram.

20% increase


Table name: Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology (12.3)]. Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see Clinical Pharmacology (12.3)]. There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole.
Table 3: Clinically Relevant Interactions Affecting Drugs Co-Administered with Omeprazole and Interaction with Diagnostics
Antiretrovirals
Clinical Impact:
The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known.
Intervention:
Rilpivirine-containing products: Concomitant use with omeprazole is contraindicated [see Contraindications (4)].
 
Atazanavir: Avoid concomitant use with omeprazole. See prescribing information for atazanavir for dosing information.
 
Nelfinavir: Avoid concomitant use with omeprazole. See prescribing information for nelfinavir.
 
Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities.
 
Other antiretrovirals: See prescribing information for specific antiretroviral drugs.
Warfarin
Clinical Impact:
Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
Intervention:
Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range.
Methotrexate
Clinical Impact:
Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions (5.11)].
Intervention:
A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate.
CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam)
Clopidogrel
Clinical Impact:
Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology (12.3)].
There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel.
Intervention:
Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy [see Warnings and Precautions (5.6)].
Citalopram
Clinical Impact:
Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology (12.3)].
Intervention:
Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.
Cilostazol
Clinical Impact:
Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology (12.3)].
Intervention:
Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.
Phenytoin
Clinical Impact:
Potential for increased exposure of phenytoin.
Intervention:
Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin.
Diazepam
Clinical Impact:
Increased exposure of diazepam [see Clinical Pharmacology (12.3)].
Intervention:
Monitor patients for increased sedation and reduce the dose of diazepam as needed.
Digoxin
Clinical Impact:
Potential for increased exposure of digoxin [see Clinical Pharmacology (12.3)].
Intervention:
Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)
Clinical Impact:
Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
Intervention:
Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF [see Clinical Pharmacology (12.3)].
 
See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact:
Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions.
Intervention:
See Contraindications, Warnings and Precautions  in prescribing information for clarithromycin.
 
See Drug Interactions in prescribing information for amoxicillin.
Tacrolimus
Clinical Impact:
Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.
Intervention:
Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact:
Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions (5.10), Clinical Pharmacology (12.2)].
Intervention:
Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
Interaction with Secretin Stimulation Test
Clinical Impact:
Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention:
Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology (12.2)].
False Positive Urine Tests for THC
Clinical Impact:
There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.
Intervention:
An alternative confirmatory method should be considered to verify positive results.
Other
Clinical Impact:
There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram).
Intervention:
Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole.


Table name:
Interacting Drug Interaction
Theophylline Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin Monitor phenytoin level (7)
Methotrexate Monitor for methotrexate toxicity (7)
Cyclosporine May increase serum creatinine. Monitor serum creatinine (7)
Multivalent cation-containing products including antacids, metal cations or didanosine Decreased CIPRO absorption. Take 2 hours before or 6 hours after CIPRO (7)


Table name:
Table 6: Effect of Other Drugs on Voriconazole Pharmacokinetics [see CLINICAL PHARMACOLOGY (12.3)]
*    Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg q12h voriconazole to healthy subjects
**  Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects
*** Non-Nucleoside Reverse Transcriptase Inhibitors
Drug/Drug Class
(Mechanism of Interaction by the Drug)
Voriconazole Plasma Exposure
(Cmax and AUCτ after 200 mg q12h)
Recommendations for Voriconazole Dosage Adjustment/Comments
Rifampin* and Rifabutin*
(CYP450 Induction)
Significantly Reduced Contraindicated
Efavirenz (400 mg q 24h)**
(CYP450 Induction)
 
Significantly Reduced Contraindicated
Efavirenz (300 mg q 24h) **
(CYP450 Induction)
Slight Decrease in AUCt When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)** (CYP450 Induction)
 
Significantly Reduced Contraindicated
Low-dose Ritonavir (100 mg q12h)** (CYP450 Induction) Reduced Coadministration of voriconazole and low-dose ritonavir (100 mg q 12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Carbamazepine
(CYP450 Induction)
Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction Contraindicated
Long Acting Barbiturates
(CYP450 Induction)
Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction Contraindicated
Phenytoin*
(CYP450 Induction)
Significantly Reduced Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100mg to 200 mg orally q12h in patients weighing less than 40 kg)
St. John’s Wort
(CYP450 inducer; P-gp inducer)
Significantly Reduced Contraindicated
Oral Contraceptives**
containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)
Increased Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole**
(CYP2C9, CYP2C19 and CYP3A4 Inhibition)
Significantly Increased Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole.
Other HIV Protease Inhibitors
(CYP3A4 Inhibition)
In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir
In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIs***
(CYP3A4 Inhibition or CYP450 Induction)
In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to voriconazole
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure) Careful assessment of voriconazole effectiveness


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
 Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration  Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
 Drugs that may alter T 4 and T 3 metabolism
 Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Drugs That Interfere with Hemostasis
Clinical Impact: Oxaprozin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of oxaprozin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of oxaprozin tablets with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].
Intervention: Concomitant use of oxaprozin tablets and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)].

Oxaprozin tablets are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: During concomitant use of oxaprozin tablets and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of oxaprozin tablets and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of oxaprozin tablets with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Digoxin
Clinical Impact: The concomitant use of oxaprozin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of oxaprozin tablets and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of oxaprozin tablets and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction) because NSAID administration may result in increased plasma levels of methotrexate, especially in patients receiving high doses of methotrexate.
Intervention: During concomitant use of oxaprozin tablets and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of oxaprozin tablets and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of oxaprozin tablets and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of oxaprozin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention: The concomitant use of oxaprozin with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of oxaprozin tablets and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of oxaprozin tablets and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.

NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.

In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Corticosteroids
Clinical Impact: Concomitant use of corticosteroids with oxaprozin tablets may increase the risk of GI ulceration or bleeding.
Intervention: Monitor patients with concomitant use of oxaprozin tablets with corticosteroids for signs of bleeding [see Warnings and Precautions (5.2)].
Glyburide
Clinical Impact: While oxaprozin does alter the pharmacokinetics of glyburide, coadministration of oxaprozin to type II non-insulin dependent diabetic patients did not affect the area under the glucose concentration curve nor the magnitude or duration of control.
Intervention: During concomitant use of oxaprozin tablets and glyburide, monitor patient’s blood glucose in the beginning phase of cotherapy.


Table name:
Table 5. Clinically-Significant Drug Interactions with Sertraline Hydrochloride
Monoamine  Oxidase  Inhibitors  ( MAOIs )
Clinical  Impact :
The concomitant use of SSRIs including sertraline hydrochloride and MAOIs increases the risk of serotonin syndrome.
Intervention :
Sertraline hydrochloride is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue  [ See  Dosage  and  Administration  ( 2 . 5 ),  Contraindications  ( 4 ),  Warnings  and  Precautions  ( 5 . 2)].
Examples :
selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue
Pimozide
Clinical  Impact :
Increased plasma concentrations of pimozide, a drug with a narrow therapeutic index, may increase the risk of QT prolongation and ventricular arrhythmias.
Intervention :
Concomitant use of pimozide and sertraline hydrochloride is contraindicated  [ See  Contraindications  ( 4)].
Other  Serotonergic  Drugs
Clinical  Impact :
The concomitant use of serotonergic drugs with sertraline hydrochloride increases the risk of serotonin syndrome.
Intervention :
Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of sertraline hydrochloride and/or concomitant serotonergic drugs  [ See  Warnings  and  Precautions  ( 5 . 2)].
Examples :
other SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort
Drugs  that  Interfere  with  Hemostasis  ( antiplatelet  agents  and  anticoagulants )
Clinical  Impact :
The concurrent use of an antiplatelet agent or anticoagulant with sertraline hydrochloride may potentiate the risk of bleeding.
Intervention :
Inform patients of the increased risk of bleeding associated with the concomitant use of sertraline hydrochloride and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio  [ See  Warnings  and  Precautions  ( 5 . 3)].
Examples :
aspirin, clopidogrel, heparin, warfarin
Drugs  Highly  Bound  to  Plasma  Protein
Clinical  Impact :
Sertraline hydrochloride is highly bound to plasma protein. The concomitant use of sertraline hydrochloride with another drug that is highly bound to plasma protein may increase free concentrations of sertraline hydrochloride or other tightly-bound drugs in plasma  [ See  Clinical  Pharmacology  ( 12 . 3 )].
Intervention :
Monitor for adverse reactions and reduce dosage of sertraline hydrochloride or other protein-bound drugs as warranted.
Examples :
warfarin
Drugs  Metabolized  by  CYP2D6
Clinical  Impact :
Sertraline hydrochloride is a CYP2D6 inhibitor  [ See  Clinical  Pharmacology  ( 12 . 3)]. The concomitant use of sertraline hydrochloride with a CYP2D6 substrate may increase the exposure of the CYP2D6 substrate.
Intervention :
Decrease the dosage of a CYP2D6 substrate if needed with concomitant sertraline hydrochloride use. Conversely, an increase in dosage of a CYP2D6 substrate may be needed if sertraline hydrochloride is discontinued.
Examples :
propafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, thoridazine, tolterodine, venlafaxine
Phenytoin
Clinical  Impact :
Phenytoin is a narrow therapeutic index drug. Sertraline hydrochloride may increase phenytoin concentrations.
Intervention :
Monitor phenytoin levels when initiating or titrating sertraline hydrochloride. Reduce phenytoin dosage if needed.
Examples :
phenytoin, fosphenytoin


Table name:
Drugs that Affect Renal Function A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDS], COX-2 inhibitors may impair the excretion of digoxin.
Antiarrthymics Dofetilide Concomitant administration with digoxin was associated with a higher rate of torsades de pointes
Sotalol Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
Dronedarone Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone Analog Teriparatide Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement Thyroid Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics Epinephrine
Norepinephrine     
Dopamine
Can increase the risk of cardiac arrhythmias
Neuromuscular Blocking Agents      Succinylcholine May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.
Supplements Calcium If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.


Table name:
 Drug  Type of Interaction  Effect**
Adenosine Theophylline blocks adenosine receptors. Higher doses of adenosine may be required to achieve desired effect.
Alcohol A single large dose of alcohol (3 ml/kg of whiskey) decreases theophylline clearance for up to 24 hours. 30% increase
Allopurinol Decreases theophylline clearance at allopurinol doses ≥600 mg/day. 25% increase
Aminoglutethimide Increases theophylline clearance by induction of microsomal enzyme activity. 25% decrease
Carbamazepine Similar to aminoglutethimide. 30% decrease
Cimetidine Decreases theophylline clearance by inhibiting cytochrome P450 1A2. 70% increase
Ciprofloxacin Similar to cimetidine. 40% increase
Clarithromycin Similar to erythromycin. 25% increase
Diazepam Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram Decreases theophylline clearance by inhibiting hydroxylation and demethylation. 50% increase
Enoxacin Similar to cimetidine. 300% increase
Ephedrine Synergistic CNS effects. Increased frequency of nausea, nervousness, and insomnia.
Erythromycin Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3. 35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown. 30% increase
 Flurazepam Similar to diazepam. Similar to diazepam.
Fluvoxamine Similar to cimetidine. Similar to cimetidine.
Halothane Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines. Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-A Decreases theophylline clearance. 100% increase
Isoproterenol (IV) Increases theophylline clearance. 20% decrease
Ketamine Pharmacologic May lower theophylline seizure threshold.
Lithium Theophylline increases renal lithium clearance. Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam Similar to diazepam. Similar to diazepam.
Methotrexate (MTX) Decreases theophylline clearance. 20% increase after low dose MTX, higher dose MTX may have a greater effect.
Mexiletine Similar to disulfiram. 80% increase
Midazolam Similar to diazepam. Similar to diazepam.
Moricizine Increases theophylline clearance. 25% decrease
Pancuronium Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition. Larger dose of pancuronium may be required to achieve neuromuscular blockade.
Pentoxifylline Decreases theophylline clearance. 30% increase
Phenobarbital (PB) Similar to aminoglutethimide. 25% decrease after two weeks of concurrent PB.
Phenytoin Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption. Serum theophylline and phenytoin concentrations decrease about 40%.
Propafenone  Decreases theophylline clearance and pharmacologic interaction. 40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Propranolol Similar to cimetidine and pharmacologic interaction. 100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Rifampin Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity. 20 to 40% decrease
Sulfinpyrazone Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline. 20% decrease
Tacrine Similar to cimetidine, also increases renal clearance of theophylline. 90% increase
 hiabendazole Decreases theophylline clearance. 190% increase
Ticlopidine Decreases theophylline clearance. 60% increase
Troleandomycin Similar to erythromycin. 33 to 100% increase depending on troleandomycin dose.
Verapamil  imilar to disulfiram. 20% increase


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
 Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)  Avoid atorvastatin
 HIV protease inhibitor (lopinavir plus ritonavir)  Use with caution and lowest dose necessary
 Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)  Do not exceed 20 mg atorvastatin daily
 HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
 Do not exceed 40 mg atorvastatin daily


Table name: Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.During concomitant use of diclofenac sodium delayed-release tablets and ACE-inhibitors, ARBs, or beta- blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of diclofenac sodium delayed-release tablets and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS: Renal Toxicity and Hyperkalemia ). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Table 2. Clinically Significant Drug Interactions with Diclofenac
Drugs That Interfere with Hemostasis
Clinical Impact:
Intervention: Monitor patients with concomitant use of diclofenac sodium delayed-release tablets with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS: Hematologic Toxicity ).
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation ).
Intervention: Concomitant use of diclofenac sodium delayed-release tablets and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS: Hematologic Toxicity ). Diclofenac sodium delayed-release tablets are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:
Intervention:
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of diclofenac sodium delayed-release tablets with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS: Renal Toxicity and Hyperkalemia ).
Digoxin
Clinical Impact: The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of diclofenac sodium delayed-release tablets and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of diclofenac sodium delayed-release tablets and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of diclofenac sodium delayed-release tablets and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of diclofenac sodium delayed-release tablets and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of diclofenac sodium delayed-release tablets and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation ).
Intervention: The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of diclofenac sodium delayed-release tablets and pemetrexed may increase the risk of pemetrexed‑ associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of diclofenac sodium delayed-release tablets and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
CYP2C9 Inhibitors or Inducers:
Clinical Impact: Diclofenac is metabolized by cytochrome P450 enzymes, predominantly by CYP2C9. Co-administration of diclofenac with CYP2C9 inhibitors (e.g. voriconazole) may enhance the exposure and toxicity of diclofenac whereas co‑administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of diclofenac.
Intervention: A dosage adjustment may be warranted when diclofenac is administered with CYP2C9 inhibitors or inducers (see CLINICAL PHARMACOLOGY: Pharmacokinetics ).


Table name:
Digoxin concentrations increased greater than 50%
Digoxin Serum Concentration Increase Digoxin AUC Increase Recommendations
Amiodarone 70% NA Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30% to 50% or by modifying the dosing frequency and continue monitoring.
Captopril 58% 39%
Clarithromycin NA 70%
Dronedarone NA 150%
Gentamicin 129 to 212% NA
Erthromycin 100% NA
Itraconazole 60% NA
Lapatinib NA 180%
Propafenone NA 60 to 270 %
Quinidine 100% NA
Ranolazine 50% NA
Ritonavir NA 86%
Telaprevir 50% 85%
Tetracycline 100% NA
Verapamil 50 to 75% NA
Digoxin concentrations increased less than 50%
Atorvastatin 22% 15% Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15% to 30% or by modifying the dosing frequency and continue monitoring.
Carvedilol 16% 14%
Conivaptan 33% 43%
Diltiazem 20% NA
Indomethacin 40% NA
Nefazodone 27% 15%
Nifedipine 45% NA
Propantheline 24% 24%
Quinine NA 33%
Rabeprazole 29% 19%
Saquinavir 27% 49%
Spironolactone 25% NA
Telmisartan 20 to 49% NA
Ticagrelor 31% 28%
Tolvaptan 30% 20%
Trimethoprim 22 to28% NA
Digoxin concentrations increased, but magnitude is unclear
Alprazolam, azithromycin, cyclosporine, diclofenac, diphenoxylate, epoprostenol, esomeprazole, ibuprofen, ketoconazole, lansoprazole, metformin, omeprazole Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin concentrations decreased
Acarbose, activated charcoal, albuterol, antacids, certain cancer chemotherapy or radiation therapy, cholestyramine, colestipol, extenatide, kaolin-pectin, meals high in bran, metoclopramide, miglitol, neomycin, penicillamine, phenytoin, rifampin, St. John’s Wort, sucralfate, and sulfasalazine Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20 % to 40 % as necessary.


Table name:
Drugs That Interfere with Hemostasis
Clinical Impact: • Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of naproxen or naproxen sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: Concomitant use of naproxen or naproxen sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen or naproxen sodium is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE-inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: • During concomitant use of naproxen or naproxen sodium and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of naproxen or naproxen sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen or naproxen sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact: The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of naproxen or naproxen sodium and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen or naproxen sodium and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of naproxen or naproxen sodium and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of naproxen or naproxen sodium and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of naproxen or naproxen sodium and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of naproxen or naproxen sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of naproxen or naproxen sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact: Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention: Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen or naproxen sodium is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed release tablets are not recommended.
Cholestyramine
Clinical Impact: Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention: Concomitant administration of cholestyramine with naproxen or naproxen sodium is not recommended.
Probenecid
Clinical Impact: Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention: Patients simultaneously receiving naproxen or naproxen sodium and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact: Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention: Patients simultaneously receiving naproxen or naproxen sodium and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.


Table name:
AED Co-administered AED Concentration Topiramate Concentration
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated
Phenytoin NC or 25% increase= Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. 48% decrease
Carbamazepine (CBZ) NC 40% decrease
CBZ epoxide= Is not administered but is an active metabolite of carbamazepine. NC NE
Valproic acid 11% decrease 14% decrease
Phenobarbital NC NE
Primidone NC NE
Lamotrigine NC at TPM doses up to 400 mg/day 13% decrease


Table name:
Drugs that Affect Renal Function A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDS], COX-2 inhibitors may impair the excretion of digoxin.
Antiarrthymics Dofetilide Concomitant administration with digoxin was associated with a higher rate of torsades de pointes
Sotalol Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
Dronedarone Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone Analog Teriparatide Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement Thyroid Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics Epinephrine
Norepinephrine     
Dopamine
Can increase the risk of cardiac arrhythmias
Neuromuscular Blocking Agents      Succinylcholine May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.
Supplements Calcium If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.
Hyperpolarization-activated cyclic nucleotide-gated channel blocker Ivabradine Can increase the risk of bradycardia


Table name:
Table II. Clinically significant drug interactions with theophylline*.
Drug Type of Interaction Effect**
Adenosine Theophylline blocks adenosine receptors. Higher doses of adenosine may be required to achieve desired effect.
Alcohol A single large dose of alcohol (3 ml/kg of whiskey) decreases theophylline clearance for up to 24 hours. 30% increase
Allopurinol Decreases theophylline clearance at allopurinol doses ≥ 600 mg/day. 25% increase
Amino glutethimide Increases theophylline clearance by induction of microsomal enzyme activity. 25% increase
Carbamazepine Similar to aminoglutethimide 30% increase
Cimetidine Decreases theophylline clearance by inhibiting cytochrome P450 1A2. 70% increase
Ciprofloxacin Similar to cimetidine. 40% increase
Clarithromycin Similar to erythromycin. 25% increase
Diazepam Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. Larger diazepam doses may be required to produce desired level of sedation.
Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram Decreases theophylline clearance by inhibiting hydroxylation and demethylation. 50% increase
Enoxacin Similar to cimetidine. 300% increase
Ephedrine Synergistic CNS effect Increased frequency of nausea, nervousness, and insomnia.
Erythromycin Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3 35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown. 30% increase
Flurazepam Similar to diazepam. Similar to diazepam.
Fluvoxamine Similar to cimetidine. Similar to cimetidine
Halothane Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines. Increase risk of ventricular arrhythmias.
Interferon,
human
recombinant
alpha-A
Decreases theophylline clearance. 100% increase
Isoproterenol
(IV)
Increases theophylline clearance. 20% decrease
Ketamine Pharmacologic May lower theophylline seizure threshold.
Lithium Theophylline increases renal lithium clearance. Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%
Lorazepam Similar to diazepam. Similar to diazepam.
Methotrexate
(MTX)
Decreases theophylline clearance. 20% increase after low dose MTX, higher dose MTX may have greater effect.
Mexiletine Similar to disulfiram. 80% increase
Midazolam Similar to diazepam. Similar to diazepam.
Moricizine Increases theophylline clearance. 25% decrease
Pancuronium Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition. Larger dose of pancuronium may be required to achieve neuromuscular blockade.
Pentoxifylline Decreases theophylline clearance. 30% increase
Phenobarbital (PB) Similar to aminoglutethimide. 25% decrease after two weeks of concurrent PB.
Phenytoin Phenytoin increase theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption. Serum theophylline and phenytoin concentrations decrease about 40%.
Propafenone Decreases theophylline clearance and pharmacologic interaction. 40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Propranolol Similar to cimetidine and pharmacologic interaction. 100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Rifampin Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity. 20-40% decrease
Sulfinpyrazone Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline. 20% decrease
Tacrine Similar to cimetidine, also increases renal clearance of theophylline. 90% increase
Thiabendazole Decreases theophylline clearance. 190% increase
Ticlopidine Decreases theophylline clearance. 60% increase
Troleandomycin Similar to erythromycin. 33-100% increase depending on troleandomycin dose.
Verapamil Similar to disulfiram. 20% increase


Table name:
Table 5. Clinically-Significant Drug Interactions with Sertraline Hydrochloride
Monoamine  Oxidase  Inhibitors  ( MAOIs )
Clinical  Impact :
The concomitant use of SSRIs including sertraline hydrochloride and MAOIs increases the risk of serotonin syndrome.
Intervention :
Sertraline hydrochloride is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [ See  Dosage  and  Administration  ( 2 . 5 ),  Contraindications  ( 4 ),  Warnings  and  Precautions  ( 5 . 2)].
Examples :
selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue
Pimozide
Clinical  Impact :
Increased plasma concentrations of pimozide, a drug with a narrow therapeutic index, may increase the risk of QT prolongation and ventricular arrhythmias.
Intervention :
Concomitant use of pimozide and sertraline hydrochloride is contraindicated [ See  Contraindications  ( 4)].
Other  Serotonergic  Drugs
Clinical  Impact :
The concomitant use of serotonergic drugs with sertraline hydrochloride increases the risk of serotonin syndrome.
Intervention :
Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of sertraline hydrochloride and/or concomitant serotonergic drugs [ See  Warnings  and  Precautions  ( 5 . 2)].
Examples :
other SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort
Drugs  that  Interfere  with  Hemostasis  ( antiplatelet  agents  and  anticoagulants )
Clinical  Impact :
The concurrent use of an antiplatelet agent or anticoagulant with sertraline hydrochloride may potentiate the risk of bleeding.
Intervention :
Inform patients of the increased risk of bleeding associated with the concomitant use of sertraline hydrochloride and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio [ See  Warnings  and  Precautions  ( 5 . 3)].
Examples :
aspirin, clopidogrel, heparin, warfarin
Drugs  Highly  Bound  to  Plasma  Protein
Clinical  Impact :
Sertraline hydrochloride is highly bound to plasma protein. The concomitant use of sertraline hydrochloride with another drug that is highly bound to plasma protein may increase free concentrations of sertraline hydrochloride or other tightly-bound drugs in plasma [ See  Clinical  Pharmacology  ( 12 . 3 )].
Intervention :
Monitor for adverse reactions and reduce dosage of sertraline hydrochloride or other protein-bound drugs as warranted.
Examples :
warfarin
Drugs  Metabolized  by  CYP2D6
Clinical  Impact :
Sertraline hydrochloride is a CYP2D6 inhibitor [ See  Clinical  Pharmacology  ( 12 . 3)]. The concomitant use of sertraline hydrochloride with a CYP2D6 substrate may increase the exposure of the CYP2D6 substrate.
Intervention :
Decrease the dosage of a CYP2D6 substrate if needed with concomitant sertraline hydrochloride use. Conversely, an increase in dosage of a CYP2D6 substrate may be needed if sertraline hydrochloride is discontinued.
Examples :
propafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, thoridazine, tolterodine, venlafaxine
Phenytoin
Clinical  Impact :
Phenytoin is a narrow therapeutic index drug. Sertraline hydrochloride may increase phenytoin concentrations.
Intervention :
Monitor phenytoin levels when initiating or titrating sertraline hydrochloride. Reduce phenytoin dosage if needed.
Examples :
phenytoin, fosphenytoin


Table name: In patients receiving STRIBILD for at least 1 week, start tadalafil at 20 mg once daily. Increase tadalafil dose to 40 mg once daily based upon individual tolerability.Coadministration of STRIBILD in patients on tadalafil: Avoid use of tadalafil during the initiation of STRIBILD. Stop tadalafil at least 24 hours prior to starting STRIBILD. After at least one week following initiation of STRIBILD, resume tadalafil at 20 mg once daily. Increase tadalafil dose to 40 mg once daily based upon individual tolerability.Use of PDE-5 inhibitors for erectile dysfunction:
Sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg in 72 hours, or tadalafil at a single dose not exceeding 10 mg in 72 hours can be used with increased monitoring for PDE-5 inhibitor associated with adverse events.
Table 6 Established and Other Potentially SignificantThis table is not all inclusive. Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction
Concomitant Drug Class: Drug Name Effect on Concentration ↑ = Increase, ↓ = Decrease, ⇔ = No Effect Clinical Comment
Acid Reducing Agents:
AntacidsIndicates that a drug-drug interaction trial was conducted. (for example aluminum and magnesium hydroxide)
↓ elvitegravir Elvitegravir plasma concentrations are lower when STRIBILD is administered simultaneously with antacids. It is recommended to separate STRIBILD and antacid administration by at least 2 hours.
Antiarrhythmics:
e.g.
amiodarone
bepridil
digoxin
disopyramide
flecainide
systemic lidocaine mexiletine
propafenone
quinidine
↑ antiarrhythmics
↑ digoxin
Concentrations of these antiarrhythmic drugs may be increased when coadministered with STRIBILD. Caution is warranted and therapeutic concentration monitoring, if available, is recommended for antiarrhythmics when coadministered with STRIBILD.
Antibacterials:
clarithromycin
telithromycin
↑ clarithromycin
↑ telithromycin
↑ cobicistat
Concentrations of clarithromycin and/or cobicistat may be altered when clarithromycin is coadministered with STRIBILD.
Patients with CLcr greater than or equal to 60 mL/minute:
No dose adjustment of clarithromycin is required.
Patients with CLcr between 50 mL/minute and 60 mL/minute:
The dose of clarithromycin should be reduced by 50%.
Concentrations of telithromycin and/or cobicistat may be increased when telithromycin is coadministered with STRIBILD.
Anticoagulants:
warfarin
Effect on warfarin unknown Concentrations of warfarin may be affected upon coadministration with STRIBILD. It is recommended that the international normalized ratio (INR) be monitored upon coadministration with STRIBILD.
Anticonvulsants:
carbamazepine
oxcarbazepine phenobarbital
phenytoin
↑ carbamazepine
↓ elvitegravir
↓ cobicistat
Coadministration of carbamazepine, oxcarbazepine, phenobarbital, or phenytoin with STRIBILD may significantly decrease cobicistat and elvitegravir plasma concentrations, which may result in loss of therapeutic effect and development of resistance. Alternative anticonvulsants should be considered.
clonazepam
ethosuximide
↑ clonazepam
↑ ethosuximide
Concentrations of clonazepam and ethosuximide may be increased when coadministered with STRIBILD. Clinical monitoring is recommended upon coadministration with STRIBILD.
Antidepressants:
Selective Serotonin Reuptake Inhibitors (SSRIs)
e.g.
paroxetine

Tricyclic
Antidepressants (TCAs)
e.g.
amitriptyline
desipramine
imipramine
nortriptyline
bupropion
trazodone
↑ SSRIs
↑ TCAs
↑ trazodone
Concentrations of these antidepressant agents may be increased when coadministered with STRIBILD. Careful dose titration of the antidepressant and monitoring for antidepressant response are recommended.
Antifungals:
itraconazole ketoconazole
voriconazole
↑ elvitegravir
↑ cobicistat
↑ itraconazole
↑ ketoconazole
↑voriconazole
Concentrations of ketoconazole, itraconazole and voriconazole may increase upon coadministration with STRIBILD. When administering with STRIBILD, the maximum daily dose of ketoconazole or itraconazole should not exceed 200 mg per day.
An assessment of benefit/risk ratio is recommended to justify use of voriconazole with STRIBILD.
Anti-gout:
colchicine
↑ colchicine STRIBILD is not recommended to be coadministered with colchicine to patients with renal or hepatic impairment.
Treatment of gout-flares – coadministration of colchicine in patients receiving STRIBILD:
0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Treatment course to be repeated no earlier than 3 days.
Prophylaxis of gout-flares – coadministration of colchicine in patients receiving STRIBILD:
If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.
Treatment of familial Mediterranean fever – coadministration of colchicine in patients receiving STRIBILD:
Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Antimycobacterial:
rifabutin
rifapentine
↓ elvitegravir
↓ cobicistat
Coadministration of rifabutin and rifapentine with STRIBILD may significantly decrease elvitegravir and cobicistat plasma concentrations, which may result in loss of therapeutic effect and development of resistance.
Coadministration of STRIBILD with rifabutin or rifapentine is not recommended.
Beta-Blockers:
e.g.
metoprolol
timolol
↑ beta-blockers Concentrations of beta-blockers may be increased when coadministered with STRIBILD. Clinical monitoring is recommended and a dose decrease of the beta blocker may be necessary when these agents are coadministered with STRIBILD.
Calcium Channel Blockers:
e.g. amlodipine
diltiazem
felodipine
nicardipine
nifedipine
verapamil
↑ calcium channel blockers Concentrations of calcium channel blockers may be increased when coadministered with STRIBILD. Caution is warranted and clinical monitoring is recommended upon coadministration with STRIBILD.
Corticosteroid:
Systemic:

dexamethasone
↓ elvitegravir
↓ cobicistat
Systemic dexamethasone, a CYP3A inducer, may significantly decrease elvitegravir and cobicistat plasma concentrations, which may result in loss of therapeutic effect and development of resistance.
Corticosteroid:
Inhaled/Nasal:

fluticasone
↑ fluticasone Concomitant use of inhaled or nasal fluticasone and STRIBILD may increase plasma concentrations of fluticasone, resulting in reduced serum cortisol concentrations. Alternative corticosteroids should be considered, particularly for long term use.
Endothelin Receptor Antagonists:
bosentan
↑ bosentan Coadministration of bosentan in patients on STRIBILD:
In patients who have been receiving STRIBILD for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Coadministration of STRIBILD in patients on bosentan:
Discontinue use of bosentan at least 36 hours prior to initiation of STRIBILD. After at least 10 days following the initiation of STRIBILD, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
HMG-CoA Reductase Inhibitors:
atorvastatin
↑ atorvastatin Initiate with the lowest starting dose of atorvastatin and titrate carefully while monitoring for safety.
Hormonal Contraceptives:
norgestimate/ethinyl estradiol
↑ norgestimate
↓ ethinyl estradiol
The effects of increases in the concentration of the progestational component norgestimate are not fully known and can include increased risk of insulin resistance, dyslipidemia, acne, and venous thrombosis. The potential risks and benefits associated with coadministration of norgestimate/ethinyl estradiol with STRIBILD should be considered, particularly in women who have risk factors for these events.
Coadministration of STRIBILD with other hormonal contraceptives (e.g., contraceptive patch, contraceptive vaginal ring, or injectable contraceptives) or oral contraceptives containing progestogens other than norgestimate has not been studied; therefore, alternative (non-hormonal) methods of contraception can be considered.
Immuno-suppressants:
e.g.
cyclosporine
sirolimus
tacrolimus
↑ immuno-suppressants Concentrations of these immunosuppressant agents may be increased when coadministered with STRIBILD. Therapeutic monitoring of the immunosuppressive agents is recommended upon coadministration with STRIBILD.
Narcotic Analgesics:
buprenorphine/
naloxone

↑ buprenorphine
↑ norbuprenorphine
↓ naloxone
Concentrations of buprenorphine and norbuprenorphine are increased when coadministered with STRIBILD. No dose adjustment of buprenorphine/naloxone is required upon coadministration with STRIBILD. Patients should be closely monitored for sedation and cognitive effects.
Inhaled Beta Agonist:
salmeterol
↑ salmeterol Coadministration of salmeterol and STRIBILD is not recommended. Coadministration of salmeterol with STRIBILD may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.
Neuroleptics:
e.g.
perphenazine
risperidone
thioridazine
↑ neuroleptics A decrease in dose of the neuroleptic may be needed when coadministered with STRIBILD.
Phosphodiesterase-5 (PDE5) Inhibitors:
sildenafil
tadalafil
vardenafil
↑ PDE5 inhibitors Coadministration with STRIBILD may result in an increase in PDE-5 inhibitor associated adverse reactions, including hypotension, syncope, visual disturbances, and priapism.
Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH): Use of sildenafil is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH). The following dose adjustments are recommended for the use of tadalafil with STRIBILD:
Coadministration of tadalafil in patients on STRIBILD:
   
Sedative/hypnotics:
Benzodiazepines:
e.g.
Parenterally administered midazolam
clorazepate
diazepam
estazolam
flurazepam
buspirone
zolpidem
↑ sedatives/hypnotics Concomitant use of parenteral midazolam with STRIBILD may increase plasma concentrations of midazolam. Coadministration should be done in a setting that ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Coadministration of oral midazolam with STRIBILD is contraindicated.
With other sedative/hypnotics, dose reduction may be necessary and clinical monitoring is recommended.


Table name:
AED  Co - administered
AED  Concentration
Topiramate 
Concentration

a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
b = Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated
Phenytoin
NC or 25% increase a
48% decrease
Carbamazepine (CBZ)
NC
40% decrease
CBZ epoxide b
NC
NE
Valproic acid
11% decrease
14% decrease
Phenobarbital
NC 
NE
Primidone
NC
NE
Lamotrigine
NC at TPM doses up to 400 mg/day
13% decrease



Table name:
Drug Interactions Associated with Increased Risk of  Myopathy/Rhabdomyolysis ( , , , , , , , ) 2.3 2.4 4 5.1 7.1 7.2 7.3 12.3
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice Avoid grapefruit juice


Table name:
Antibiotics Anticonvulsants Other Drugs /   Dietary Supplements
nafcillin carbamazepine bosentan St. John’s Wort
rifampin oxcarbazepine octreotide 
phenobarbital  orlistat 
phenytoin sulfinpyrazone 
terbinafine 
ticlopidine


Table name:
Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast,
moricizine,
omeprazole, phenobarbital, phenytoin,
cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir,
aprepitant,
bosentan,
carbamazepine, efavirenz,
etravirine,
modafinil, nafcillin,
phenytoin,
pioglitazone, prednisone,
rifampin,
rufinamide


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion –the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine / Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing
Radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing
Radiographic contrast agents)
Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T4 and T3 serum transport - but FT4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4 , 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.12 , 7.3)


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
 Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration  Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
 Drugs that may alter T 4 and T 3 metabolism
 Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
 AED  Co - administered
 AED  Concentration
 Topiramate  Concentration
 Phenytoin
 NCor25%increasea
 48%decrease
 Carbamazepine(CBZ)
 NC
 40%decrease
 CBZepoxideb
 NC 
             NE
 Valproic acid
 11%decrease
 14%decrease
 Phenobarbital
 NC
             NE
 Primidone
 NC
            NE
 Lamotrigine
 NCatTPM dosesupto400  mg/day 
          13%decrease


Table name:
Concomitant Drug Name or Drug Class
Clinical Rationale
Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) 
The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].
With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)
The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].
With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Antihypertensive Drugs
Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.
Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.9)]. 
Benzodiazepines (e.g., lorazepam)
The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.9)]
Monitor sedation and blood pressure. Adjust dose accordingly.


Table name:
Concomitant Drug Name or Drug Class
Clinical Rationale
Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) 
The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].
With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)
The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].
With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Antihypertensive Drugs
Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.
Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.7)]. 
Benzodiazepines (e.g., lorazepam)
The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.7)]
Monitor sedation and blood pressure. Adjust dose accordingly.


Table name:
Laboratory Tests Effect of Salicylates
Thyroid Function Decreased PBI; increased T3 uptake
Urinary Sugar False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5 g qd)
5 Hydroxyindole Acetic Acid False negative with fluorometric test
Acetone, Ketone Bodies False positive FeCl3 in Gerhardt reaction; red color persists with boiling
17-OH corticosteroids False reduced values with >4.8 g qd salicylate
Vanilmandelic Acid False reduced values
Uric Acid May increase or decrease depending on dose
Prothrombin Decreased levels; slightly increased prothrombin time


Table name:
Bleeding times
Clinical Impact: Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention: This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact: The administration of naproxen may result in increased urinary values for 17 ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention: Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact: Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention: This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.


Table name:
Antibiotics
ciprofloxacin
gentamicin
tobramycin
trimethoprim with sulfamethoxazole
vancomycin
Antineoplastic
melphalan
 
 
 
Antifungals
amphotericin B
ketoconazole
Anti-Inflammatory Drugs
azapropazon
colchicine
diclofenac
naproxen
sulindac
Gastrointestinal Agents
cimetidine
ranitidine
 
 
Immunosuppressives
tacrolimus
 
Other Drugs
fibric acid derivatives
  (e.g., bezafibrate, fenofibrate)


Table name:
Table 9. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class:
Drug Name
Effect on Concentration of Lopinavir or Concomitant Drug Clinical Comments
HIV-1 Antiviral Agents
Non-nucleoside Reverse Transcriptase Inhibitors:
efavirenz*,
nevirapine*
↓ lopinavir KALETRA dose increase is recommended in all patients [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
Increasing the dose of KALETRA tablets to 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) twice daily co-administered with efavirenz resulted in similar lopinavir concentrations compared to KALETRA tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz.
Increasing the dose of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice daily co-administered with efavirenz resulted in significantly higher lopinavir plasma concentrations compared to KALETRA tablets 400/100 mg twice daily without efavirenz.
KALETRA should not be administered once daily in combination with efavirenz or nevirapine
[see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
Non-nucleoside Reverse Transcriptase Inhibitor:
delavirdine
↑ lopinavir Appropriate doses of the combination with respect to safety and efficacy have not been established.
Nucleoside Reverse Transcriptase Inhibitor:
didanosine
  KALETRA tablets can be administered simultaneously with didanosine without food.
For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food).
Nucleoside Reverse Transcriptase Inhibitor:
tenofovir
↑ tenofovir KALETRA increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir.
Nucleoside Reverse Transcriptase Inhibitor:
abacavir
zidovudine
↓ abacavir
↓ zidovudine
KALETRA induces glucuronidation; therefore, KALETRA has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown.
HIV-1 Protease Inhibitor:
amprenavir*
↑ amprenavir
↓ lopinavir
KALETRA should not be administered once daily in combination with amprenavir
[see Dosage and Administration (2.1)].
HIV-1 Protease Inhibitor:
fosamprenavir/ritonavir
↓ amprenavir
↓ lopinavir
An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor:
indinavir*
↑ indinavir Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily [see Clinical Pharmacology (12.3)]. KALETRA once daily has not been studied in combination with indinavir.
HIV-1 Protease Inhibitor:
nelfinavir*
↑ nelfinavir
↑ M8 metabolite of nelfinavir
↓ lopinavir
KALETRA should not be administered once daily in combination with nelfinavir
[see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].

HIV-1 Protease Inhibitor:
ritonavir*
↑ lopinavir Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor:
saquinavir*
↑ saquinavir The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily.
KALETRA once daily has not been studied in combination with saquinavir.
HIV-1 Protease Inhibitor:
tipranavir
↓ lopinavir AUC and Cmin KALETRA should not be administered with tipranavir (500 mg twice daily) co-administered with ritonavir (200 mg twice daily).
HIV CCR5 – Antagonist:
maraviroc
↑ maraviroc Concurrent administration of maraviroc with KALETRA will increase plasma levels of maraviroc. When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for Selzentry® (maraviroc).
Other Agents
Antiarrhythmics:
amiodarone,
bepridil,
lidocaine (systemic),
quinidine
↑ antiarrhythmics Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA.
Anticancer Agents:
vincristine,
vinblastine,
dasatinib,
nilotinib
↑ anticancer agents Concentrations of these drugs may be increased when co-administered with KALETRA resulting in the potential for increased adverse events usually associated with these anticancer agents.
For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when KALETRA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor.
A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as KALETRA. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions.
Anticoagulant:
warfarin
  Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants:
carbamazepine,
phenobarbital,
phenytoin
↓ lopinavir
↓ phenytoin
KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution.
KALETRA should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin.

In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA.
Antidepressant:
bupropion
↓ bupropion
↓ active metabolite,
hydroxybupropion
Concurrent administration of bupropion with KALETRA may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion.
Antidepressant:
trazodone
↑ trazodone Concomitant use of trazodone and KALETRA may increase concentrations of trazodone. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered.
Anti-infective:
clarithromycin
↑ clarithromycin For patients with renal impairment, the following dosage adjustments should be considered:
  • For patients with CLCR 30 to 60 mL/min the dose
    of clarithromycin should be reduced by 50%.
  • For patients with CLCR < 30 mL/min the dose
    of clarithromycin should be decreased by 75%.

No dose adjustment for patients with normal renal function is necessary.
Antifungals:
ketoconazole*,
itraconazole,
voriconazole
↑ ketoconazole
↑ itraconazole
↓ voriconazole
High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended.
Co-administration of voriconazole with KALETRA has not been studied. However, a study has been shown that administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%; therefore, co-administration of KALETRA and voriconazole may result in decreased voriconazole concentrations and the potential for decreased voriconazole effectiveness and should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Otherwise, alternative antifungal therapies should be considered in these patients.
Anti-gout:
colchicine
↑ colchicine Patients with renal or hepatic impairment should not be given colchicine with KALETRA.

Treatment of gout flares-co-administration of colchicine in patients on KALETRA:

0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days.

Prophylaxis of gout flares-co-administration of colchicine in patients on KALETRA:

If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.

If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.

Treatment of familial Mediterranean fever (FMF)-co-administration of colchicine in patients on KALETRA:

Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Antimycobacterial:
rifabutin*
↑ rifabutin and rifabutin metabolite Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary.
Antimycobacterial:
rifampin
↓ lopinavir May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents. A study evaluated combination of rifampin 600 mg once daily, with KALETRA 800/200 mg twice daily or KALETRA 400/100 mg + ritonavir 300 mg twice daily. Pharmacokinetic and safety results from this study do not allow for a dose recommendation. Nine subjects (28%) experienced a ≥ grade 2 increase in ALT/AST, of which seven (21%) prematurely discontinued study per protocol. Based on the study design, it is not possible to determine whether the frequency or magnitude of the ALT/AST elevations observed is higher than what would be seen with rifampin alone [see Clinical Pharmacology (12.3) for magnitude of interaction].
Antiparasitic:
atovaquone
↓ atovaquone Clinical significance is unknown; however, increase in atovaquone doses may be needed.
Benzodiazepines: parenterally administered midazolam ↑ midazolam Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, KALETRA should not be given with orally administered midazolam [see Contraindications (4)]. If KALETRA is co-administered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.
Calcium Channel Blockers:
dihydropyridine,
felodipine,
nifedipine,
nicardipine
↑ dihydropyridine calcium channel blockers Caution is warranted and clinical monitoring of patients is recommended.
Contraceptive:
ethinyl estradiol*
↓ ethinyl estradiol Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended.
Corticosteroid:
dexamethasone

↓ lopinavir Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly.


disulfiram/metronidazole   KALETRA oral solution contains alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).
Endothelin Receptor Antagonists:
bosentan
↑ bosentan Co-administration of bosentan in patients on KALETRA:

In patients who have been receiving KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

Co-administration of KALETRA in patients on bosentan:

Discontinue use of bosentan at least 36 hours prior to initiation of KALETRA.

After at least 10 days following the initiation of KALETRA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
HMG-CoA Reductase Inhibitors:
atorvastatin
rosuvastatin
↑ atorvastatin
↑ rosuvastatin
Use atorvastatin with caution and at the lowest necessary dose. Titrate rosuvastatin dose carefully and use the lowest necessary dose; do not exceed rosuvastatin 10 mg/day. See Drugs with No Observed or Predicted Interactions with KALETRA (7.4) and Clinical Pharmacology (12.3) for drug interaction data with other HMG-CoA reductase inhibitors.
Immunosuppressants:
cyclosporine,
tacrolimus,
rapamycin
↑ immunosuppressants Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA.
Inhaled Steroid:
fluticasone
↑ fluticasone Concomitant use of fluticasone propionate and KALETRA may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during post-marketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Co-administration of fluticasone propionate and KALETRA is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effect.
Long-acting beta-adrenoceptor Agonist:
salmeterol
↑ salmeterol Concurrent administration of salmeterol and KALETRA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Narcotic Analgesic:
methadone*
fentanyl
↓ methadone
↑ fentanyl
Dosage of methadone may need to be increased when co-administered with KALETRA.
Concentrations of fentanyl are expected to increase. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with KALETRA.
PDE5 inhibitors:
sildenafil,
tadalafil,
vardenafil
↑ sildenafil
↑ tadalafil
↑ vardenafil
Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs is expected to substantially increase their concentrations and may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection.

Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH):

Sildenafil (Revatio®) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with KALETRA [see Contraindications (4)].

The following dose adjustments are recommended for use of tadalafil (Adcirca®) with KALETRA:

Co-administration of ADCIRCA in patients on KALETRA:

In patients receiving KALETRA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Co-administration of KALETRA in patients on ADCIRCA:

Avoid use of ADCIRCA during the initiation of KALETRA. Stop ADCIRCA at least 24 hours prior to starting KALETRA. After at least one week following the initiation of KALETRA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Use of PDE5 inhibitors for erectile dysfunction:

It is recommended not to exceed the following doses:
  • Sildenafil: 25 mg every 48 hours
  • Tadalafil: 10 mg every 72 hours
  • Vardenafil: 2.5 mg every 72 hours

Use with increased monitoring for adverse events.
*   see Clinical Pharmacology (12.3) for magnitude of interaction.


Table name:
Table 2: Drug-Thyroidal Axis Interactions
   Drug or Drug Class    Effect
   Drugs that may reduce TSH secretion–the reduction is not sustained; therefore, hypothyroidism does not occur
  Dopamine / Dopamine Agonists
Glucocorticoids
Octreotide
  Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day).
   Drugs that alter thyroid hormone secretion
   Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
  Aminoglutethimide
Amiodarone
Iodide(including iodine-containing
  Radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
  Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients.  The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T 4 and T 3 levels and increase TSH, although all values remain within normal limits in most patients.
   Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
  Amiodarone
Iodide(including iodine-containing   
  Radiographic contrast agents)
  Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma).  Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
   Drugs that may decrease T 4 absorption, which may result in hypothyroidism
  Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
  Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism.  Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents.  Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
   Drugs that may alter T 4 and T 3 serum transport  - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
   Drugs that may increase serum TBG concentration    Drugs that may decrease serum TBG concentration
  Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
  Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
   Drugs that may cause protein-binding site displacement
  Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
  Administration of these agents with levothyroxine results in an initial transient increase in FT 4. Continued administration results in a decrease in serum T 4, and normal FT 4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T 4 and T 3 to TBG and transthyretin. An initial increase in serum FT 4 is followed by return of FT 4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T 4 levels may decrease by as much as 30%.
   Drugs that may alter T 4 and T 3 metabolism
   Drugs that may increase hepatic metabolism, which may result  in hypothyroidism
  Carbamazepine
Hydantoins
Phenobarbital
Rifampin
  Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T 4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
   Drugs that may decrease T 4 5’-deiodinase activity
  Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
  Administration of these enzyme inhibitors decreases the peripheral conversion of T 4 to T 3, leading to decreased T 3 levels. However, serum T 4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T 3 and T 4  levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T 3 concentrations by 30% with minimal change in serum T 4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T 3 and T 4 levels due to decreased TBG production (see above).
   Miscellaneous
  Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
  Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
  Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors
  (SSRIs; e.g., Sertraline)
  Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of  tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
  Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
  Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
  Cardiac Glycosides   Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
  Cytokines
- Interferon-α
- Interleukin-2
  Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
  Growth Hormones
- Somatrem
- Somatropin
  Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
  Ketamine   Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
  Methylxanthine Bronchodilators
- (e.g., Theophylline)
  Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
  Radiographic Agents   Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
  Sympathomimetics   Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
  Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
  These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.


Table name:
Table 7 Summary of AED Interactions with Oxcarbazepine Tablets, USP
AED Coadministered Dose of AED
(mg/day)
Oxcarbazepine Tablets Dose
(mg/day)
Influence of Oxcarbazepine Tablets on AED Concentration
(Mean Change, 90% Confidence Interval)
Influence of AED on MHD Concentration
(Mean Change, 90% Confidence Interval)
Carbamazepine 400-2000 900 nc nc denotes a mean change of less than 10% 40% decrease
[CI: 17% decrease, 57% decrease]
Phenobarbital 100-150 600-1800 14% increase
[CI: 2% increase, 24% increase]
25% decrease
[CI: 12% decrease, 51% decrease]
Phenytoin 250-500 600-1800
>1200-2400
nc , Pediatrics up to 40% increase Mean increase in adults at high oxcarbazepine tablets, USP doses
[CI: 12% increase, 60% increase]
30% decrease
[CI: 3% decrease, 48% decrease]
Valproic acid 400-2800 600-1800 nc 18% decrease
[CI: 13% decrease, 40% decrease]


Table name:
Table 3: Clinically Significant Drug Interactions with Celecoxib
 Drugs That Interfere w ith Hemostasis
Clinical Impact:
Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of Celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:
Monitor patients with concomitant use of celecoxib with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11) ].
 Aspirin
Clinical Impact:
Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2) ].
In two studies in healthy volunteers, and in patients with osteoarthritis and established heart disease respectively, celecoxib (200 to 400 mg daily) has demonstrated a lack of interference with the cardioprotective antiplatelet effect of aspirin (100 to 325 mg).
Intervention:
Concomitant use of celecoxib and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11) ].
Celecoxib is not a substitute for low dose aspirin for cardiovascular protection.
 ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:
NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:
During concomitant use of celecoxib and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of celecoxib and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6) ]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
 Diuretics
Clinical Impact:
Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:
During concomitant use of celecoxib with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6) ].
 Digoxin
Clinical Impact:
The concomitant use of Celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:
During concomitant use of celecoxib and digoxin, monitor serum digoxin levels.
 Lithium
Clinical Impact:
NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:
During concomitant use of celecoxib and lithium, monitor patients for signs of lithium toxicity.
 Methotrexate
Clinical Impact:
Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Celecoxib has no effect on methotrexate pharmacokinetics.
Intervention:
During concomitant use of celecoxib and methotrexate, monitor patients for methotrexate toxicity.
 Cyclosporine
Clinical Impact:
Concomitant use of celecoxib and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:
During concomitant use of celecoxib and cyclosporine, monitor patients for signs of worsening renal function.
 NSAIDs a nd Salicylates
Clinical Impact:
Concomitant use of Celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2) ].
Intervention:
The concomitant use of Celecoxib with other NSAIDs or salicylates is not recommended.
 Pemetrexed
Clinical Impact:
Concomitant use of celecoxib and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:
During concomitant use of celecoxib and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.
NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.
In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
 CYP2C9 Inhibitors or inducers
Clinical Impact:
Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Co­-administration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of celecoxib.
Intervention
Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers. [see Clinical Pharmacology (12.3) ].
 CYP2D6 substrates
Clinical Impact:
In vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6 (e.g. atomoxetine), and celecoxib may enhance the exposure and toxicity of these drugs.
Intervention
Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2D6 substrates. [see Clinical Pharmacology (12.3) ].
 Corticosteroids
Clinical Impact:
Concomitant use of corticosteroids with celecoxib may increase the risk of GI ulceration or bleeding.
Intervention
Monitor patients with concomitant use of celecoxib with corticosteroids for signs of bleeding [see Warnings and Precautions (5.2) ].


Table name:
Interacting Drug
Interaction
Multivalent cation-containing products including: antacids, sucralfate, multivitamins
Decreased moxifloxacin hydrochloride absorption. Take moxifloxacin hydrochloride tablet at least 4 hours before or 8 hours after these products. (2.2, 7.1, 12.3)
Warfarin
Anticoagulant effect enhanced. Monitor prothrombin time/INR, and bleeding. (6, 7.2, 12.3)
Class IA and Class III antiarrhythmics:
Proarrhythmic effect may be enhanced. Avoid concomitant use. (5.6, 7.5)
Antidiabetic agents
Carefully monitor blood glucose. (5.11, 7.3)


Table name:
Concomitant Drug Name or Drug Class Clinical Rationale Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) The concomitant use of aripiprazole with strong CYP3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)] . With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)] .
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin) The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)] . With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)] .
Antihypertensive Drugs Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.7)] .
Benzodiazepines(e.g., lorazepam) The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.7)] . Monitor sedation and blood pressure. Adjust dose accordingly.


Table name: In patients receiving STRIBILD for at least 1 week, start tadalafil at 20 mg once daily. Increase tadalafil dose to 40 mg once daily based upon individual tolerability.Coadministration of STRIBILD in patients on tadalafil: Avoid use of tadalafil during the initiation of STRIBILD. Stop tadalafil at least 24 hours prior to starting STRIBILD. After at least one week following initiation of STRIBILD, resume tadalafil at 20 mg once daily. Increase tadalafil dose to 40 mg once daily based upon individual tolerability.Use of PDE-5 inhibitors for erectile dysfunction:
Sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg in 72 hours, or tadalafil at a single dose not exceeding 10 mg in 72 hours can be used with increased monitoring for PDE-5 inhibitor associated with adverse events.
Table 6 Established and Other Potentially SignificantThis table is not all inclusive. Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction
Concomitant Drug Class: Drug Name Effect on Concentration ↑ = Increase, ↓ = Decrease, ⇔ = No Effect Clinical Comment
Acid Reducing Agents:
AntacidsIndicates that a drug-drug interaction trial was conducted. (for example aluminum and magnesium hydroxide)
↓ elvitegravir Elvitegravir plasma concentrations are lower when STRIBILD is administered simultaneously with antacids. It is recommended to separate STRIBILD and antacid administration by at least 2 hours.
Antiarrhythmics:
e.g.
amiodarone
bepridil
digoxin
disopyramide
flecainide
systemic lidocaine mexiletine
propafenone
quinidine
↑ antiarrhythmics
↑ digoxin
Concentrations of these antiarrhythmic drugs may be increased when coadministered with STRIBILD. Caution is warranted and therapeutic concentration monitoring, if available, is recommended for antiarrhythmics when coadministered with STRIBILD.
Antibacterials:
clarithromycin
telithromycin
↑ clarithromycin
↑ telithromycin
↑ cobicistat
Concentrations of clarithromycin and/or cobicistat may be altered when clarithromycin is coadministered with STRIBILD.
Patients with CLcr greater than or equal to 60 mL/min:
No dose adjustment of clarithromycin is required.
Patients with CLcr between 50 mL/min and 60 mL/min:
The dose of clarithromycin should be reduced by 50%.
Concentrations of telithromycin and/or cobicistat may be increased when telithromycin is coadministered with STRIBILD.
Anticoagulants:
warfarin
Effect on warfarin unknown Concentrations of warfarin may be affected upon coadministration with STRIBILD. It is recommended that the international normalized ratio (INR) be monitored upon coadministration with STRIBILD.
Anticonvulsants:
carbamazepine
oxcarbazepine phenobarbital
phenytoin
↑ carbamazepine
↓ elvitegravir
↓ cobicistat
Coadministration of carbamazepine, oxcarbazepine, phenobarbital, or phenytoin with STRIBILD may significantly decrease cobicistat and elvitegravir plasma concentrations, which may result in loss of therapeutic effect and development of resistance. Alternative anticonvulsants should be considered.
clonazepam
ethosuximide
↑ clonazepam
↑ ethosuximide
Concentrations of clonazepam and ethosuximide may be increased when coadministered with STRIBILD. Clinical monitoring is recommended upon coadministration with STRIBILD.
Antidepressants:
Selective Serotonin Reuptake Inhibitors (SSRIs)
e.g.
paroxetine

Tricyclic
Antidepressants (TCAs)
e.g.
amitriptyline
desipramine
imipramine
nortriptyline
buproprion
trazodone
↑ SSRIs
↑ TCAs
↑ trazodone
Concentrations of these antidepressant agents may be increased when coadministered with STRIBILD. Careful dose titration of the antidepressant and monitoring for antidepressant response are recommended.
Antifungals:
itraconazole ketoconazole
voriconazole
↑ elvitegravir
↑ cobicistat
↑ itraconazole
↑ ketoconazole
↑voriconazole
Concentrations of ketoconazole, itraconazole and voriconazole may increase upon coadministration with STRIBILD. When administering with STRIBILD, the maximum daily dose of ketoconazole or itraconazole should not exceed 200 mg per day.
An assessment of benefit/risk ratio is recommended to justify use of voriconazole with STRIBILD.
Anti-gout:
colchicine
↑ colchicine STRIBILD is not recommended to be coadministered with colchicine to patients with renal or hepatic impairment.
Treatment of gout-flares – coadministration of colchicine in patients receiving STRIBILD:
0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Treatment course to be repeated no earlier than 3 days.
Prophylaxis of gout-flares – coadministration of colchicine in patients receiving STRIBILD:
If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.
Treatment of familial Mediterranean fever – coadministration of colchicine in patients receiving STRIBILD:
Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Antimycobacterial:
rifabutin
rifapentine
↓ elvitegravir
↓ cobicistat
Coadministration of rifabutin and rifapentine with STRIBILD may significantly decrease elvitegravir and cobicistat plasma concentrations, which may result in loss of therapeutic effect and development of resistance.
Coadministration of STRIBILD with rifabutin or rifapentine is not recommended.
Beta-Blockers:
e.g.
metoprolol
timolol
↑ beta-blockers Concentrations of beta-blockers may be increased when coadministered with STRIBILD. Clinical monitoring is recommended and a dose decrease of the beta blocker may be necessary when these agents are coadministered with STRIBILD.
Calcium Channel Blockers:
e.g. amlodipine
diltiazem
felodipine
nicardipine
nifedipine
verapamil
↑ calcium channel blockers Concentrations of calcium channel blockers may be increased when coadministered with STRIBILD. Caution is warranted and clinical monitoring is recommended upon coadministration with STRIBILD.
Corticosteroid:
Systemic:

dexamethasone
↓ elvitegravir
↓ cobicistat
Systemic dexamethasone, a CYP3A inducer, may significantly decrease elvitegravir and cobicistat plasma concentrations, which may result in loss of therapeutic effect and development of resistance.
Corticosteroid:
Inhaled/Nasal:

fluticasone
↑ fluticasone Concomitant use of inhaled or nasal fluticasone and STRIBILD may increase plasma concentrations of fluticasone, resulting in reduced serum cortisol concentrations. Alternative corticosteroids should be considered, particularly for long term use.
Endothelin Receptor Antagonists:
bosentan
↑ bosentan Coadministration of bosentan in patients on STRIBILD:
In patients who have been receiving STRIBILD for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Coadministration of STRIBILD in patients on bosentan:
Discontinue use of bosentan at least 36 hours prior to initiation of STRIBILD. After at least 10 days following the initiation of STRIBILD, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
HMG-CoA Reductase Inhibitors:
atorvastatin
↑ atorvastatin Initiate with the lowest starting dose of atorvastatin and titrate carefully while monitoring for safety.
Hormonal Contraceptives:
norgestimate/ethinyl estradiol
↑ norgestimate
↓ ethinyl estradiol
The effects of increases in the concentration of the progestational component norgestimate are not fully known and can include increased risk of insulin resistance, dyslipidemia, acne, and venous thrombosis. The potential risks and benefits associated with coadministration of norgestimate/ethinyl estradiol with STRIBILD should be considered, particularly in women who have risk factors for these events.
Coadministration of STRIBILD with other hormonal contraceptives (e.g., contraceptive patch, contraceptive vaginal ring, or injectable contraceptives) or oral contraceptives containing progestogens other than norgestimate has not been studied; therefore, alternative (non-hormonal) methods of contraception can be considered.
Immuno-suppressants:
e.g.
cyclosporine
sirolimus
tacrolimus
↑ immuno-suppressants Concentrations of these immunosuppressant agents may be increased when coadministered with STRIBILD. Therapeutic monitoring of the immunosuppressive agents is recommended upon coadministration with STRIBILD.
Narcotic Analgesics:
buprenorphine/
naloxone

↑ buprenorphine
↑ norbuprenorphine
↓ naloxone
Concentrations of buprenorphine and norbuprenorphine are increased when coadministered with STRIBILD. No dose adjustment of buprenorphine/naloxone is required upon coadministration with STRIBILD. Patients should be closely monitored for sedation and cognitive effects.
Inhaled Beta Agonist:
salmeterol
↑ salmeterol Coadministration of salmeterol and STRIBILD is not recommended. Coadministration of salmeterol with STRIBILD may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.
Neuroleptics:
e.g.
perphenazine
risperidone
thioridazine
↑ neuroleptics A decrease in dose of the neuroleptic may be needed when coadministered with STRIBILD.
Phosphodiesterase-5 (PDE5) Inhibitors:
sildenafil
tadalafil
vardenafil
↑ PDE5 inhibitors Coadministration with STRIBILD may result in an increase in PDE-5 inhibitor associated adverse reactions, including hypotension, syncope, visual disturbances, and priapism.
Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH): Use of sildenafil is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH). The following dose adjustments are recommended for the use of tadalafil with STRIBILD:
Coadministration of tadalafil in patients on STRIBILD:
   
Sedative/hypnotics:
Benzodiazepines:
e.g.
Parenterally administered midazolam
clorazepate
diazepam
estazolam
flurazepam
buspirone
zolpidem
↑ sedatives/hypnotics Concomitant use of parenteral midazolam with STRIBILD may increase plasma concentrations of midazolam. Coadministration should be done in a setting that ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Coadministration of oral midazolam with STRIBILD is contraindicated.
With other sedative/hypnotics, dose reduction may be necessary and clinical monitoring is recommended.


Table name:
Table 7. Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction
Concomitant Drug Class: Drug Name Effect on Concentration of Delavirdine or Concomitant Drug Clinical Comment
HIV-Antiviral Agents
Amprenavir ↑Amprenavir Appropriate doses of this combination with respect to safety, efficacy, and pharmacokinetics have not been established.
Didanosinea ↓Delavirdine↓Didanosine Administration of didanosine (buffered tablets) and RESCRIPTOR should be separated by at least 1 hour.
Indinavira ↑Indinavir A dose reduction of indinavir to 600 mg 3 times daily should be considered when RESCRIPTOR and indinavir are coadministered.
Lopinavir/Ritonavir ↑Lopinavir↑Ritonavir Appropriate doses of this combination with respect to safety, efficacy, and pharmacokinetics have not been established.
Nelfinavira ↑Nelfinavir↓Delavirdine Appropriate doses of this combination with respect to safety, efficacy, and pharmacokinetics have not been established. (See CLINICAL PHARMACOLOGY: Tables 1 and 2.)
Ritonavir ↑Ritonavir Appropriate doses of this combination with respect to safety, efficacy, and pharmacokinetics have not been established.
Saquinavira ↑Saquinavir A dose reduction of saquinavir (soft gelatin capsules) may be considered when RESCRIPTOR and saquinavir are coadministered (see CLINICAL PHARMACOLOGY: Table 1). Appropriate doses with respect to safety, efficacy, and pharmacokinetics have not been established.
Other Agents
Acid blockers: Antacidsa ↓Delavirdine Doses of an antacid and RESCRIPTOR should be separated by at least 1 hour, because the absorption of delavirdine is reduced when coadministered with antacids.
Histamine H2-receptor antagonists: Cimetidine, famotidine, nizatidine, ranitidine ↓Delavirdine These agents increase gastric pH and may reduce the absorption of delavirdine. Although the effect of these drugs on delavirdine absorption has not been evaluated, chronic use of these drugs with RESCRIPTOR is not recommended.
Proton pump inhibitors: Omeprazole, lansoprazole ↓Delavirdine These agents increase gastric pH and may reduce the absorption of delavirdine. Although the effect of these drugs on delavirdine absorption has not been evaluated, chronic use of these drugs with RESCRIPTOR is not recommended.
Amphetamines ↑Amphetamines Use with caution.
Antidepressant: Trazodone ↑Trazodone Concomitant use of trazodone and RESCRIPTOR may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as RESCRIPTOR, the combination should be used with caution and a lower dose of trazadone should be considered.
Antiarrhythmics: Bepridil ↑Antiarrhythmics Use with caution. Increased bepridil exposure may be associated with life-threatening reactions such as cardiac arrhythmias.
Amiodarone,lidocaine (systemic), quinidine, flecainide, propafenone Caution is warranted and therapeutic concentration monitoring is recommended, if available, for antiarrhythmics when coadministered with RESCRIPTOR.
Anticoagulant: Warfarin ↑Warfarin It is recommended that INR (international normalized ratio) be monitored.
Anti-infective: Clarithromycina ↑Clarithromycin When coadministered with RESCRIPTOR, clarithromycin should be adjusted in patients with impaired renal function: For patients with CLCR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients with CLCR <30 mL/min the dose of clarithromycin should be reduced by 75%.
Calcium channel blockers: Amlodipine, diltiazem, felodipine, isradipine, nifedipine, nicardipine, nimodipine, nisoldipine, verapamil ↑Calcium channel blockers Caution is warranted and clinical monitoring of patients is recommended.
Corticosteroid: Dexamethasone ↓Delavirdine Use with caution. RESCRIPTOR may be less effective due to decreased delavirdine plasma concentrations in patients taking these agents concomitantly.
Erectile dysfunction agents: Sildenafil ↑Sildenafil Sildenafil should not exceed a maximum single dose of 25 mg in a 48-hour period.
HMG-CoA reductase inhibitors: Atorvastatin, cerivastatin, fluvastatin ↑Atorvastatin ↑Cerivastatin↑Fluvastatin Use lowest possible dose of atorvastatin or cerivastatin, or fluvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin in combination with RESCRIPTOR.
Immunosuppressants: Cyclosporine, tacrolimus, rapamycin ↑Immunosuppressants Therapeutic concentration monitoring is recommended for immunosuppressant agents when coadministered with RESCRIPTOR.
Inhaled/nasal steroid: Fluticasone ↑Fluticasone Concomitant use of fluticasone propionate and RESCRIPTOR may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use.
Narcotic analgesic: Methadone ↑Methadone Dosage of methadone may need to be decreased when coadministered with RESCRIPTOR.
Oral contraceptives: Ethinyl estradiol ↑Ethinyl estradiol Concentrations of ethinyl estradiol may increase. However, the clinical significance is unknown.


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( 7.2)
Antidiabetic agents Carefully monitor blood glucose ( 5.12, 7.3)


Table name:
Interacting Drug Interaction
Theophylline
Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin
Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents
Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin
Monitor phenytoin level (7)
Methotrexate
Monitor for methotrexate toxicity (7)
Cyclosporine
May increase serum creatinine. Monitor serum creatinine (7)


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.11, 7.3)


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide

Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide






Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T and T levels and increase TSH, although all values remain within normal limits in most patients. 4 3
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate










Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
  Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration   Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen





Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid


Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)





Administration of these agents with levothyroxine results in an initial transient increase in FT . Continued administration results in a decrease in serum T and normal FT and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T and T to TBG and transthyretin. An initial increase in serum FT , is followed by return of FT to normal levels with sustained therapeutic serum salicylate concentrations, although total-T levels may decrease by as much as 30%. 4 4 4 4 3 4 4 4
  Drugs that may alter T 4 and T 3 metabolism
  Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin


Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. 4
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)




Administration of these enzyme inhibitors decrease the peripheral conversion of T to T , leading to decreased T levels. However, serum T levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T and T levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T concentrations by 30% with minimal change in serum T levels. However, long-term glucocorticoid therapy may result in slightly decreased T and T levels due to decreased TBG production (see above). 4 3 3 4 3 4 3 4 3 4
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives

Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)


Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin




Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2

Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin

Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of I, I, and Tc. 123 131 99m
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics









These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.10, 7.3)


Table name:
Table 7:  Summary of AED Interactions with TRILEPTAL
AED
Coadministered
Dose of AED
(mg/day)
TRILEPTAL Dose
(mg/day)
Influence of
TRILEPTAL on AED
Concentration

(Mean Change,

90% Confidence

Interval)
Influence of
AED on MHD

Concentration

(Mean Change,

90% Confidence

Interval)
Carbamazepine 400-2000 900 nc1 40% decrease
[CI: 17% decrease,
57% decrease]
Phenobarbital 100-150 600-1800 14% increase
[CI: 2% increase,
24% increase]
25% decrease
[CI: 12% decrease,
51% decrease]
Phenytoin 250-500 600-1800
>1200-2400
nc1,2
up to 40%
increase3 
[CI: 12% increase,
60% increase]
30% decrease
[CI: 3% decrease,
48% decrease]
Valproic acid 400-2800 600-1800 nc1 18% decrease
[CI: 13% decrease,
40% decrease]
Lamotrigine 200 1200 nc1 nc1


Table name:
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
 Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)  Avoid atorvastatin
 HIV protease inhibitor (lopinavir plus ritonavir)  Use with caution and lowest dose necessary
 Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)  Do not exceed 20 mg atorvastatin daily
 HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
 Do not exceed 40 mg atorvastatin daily


Table name:
AED Coadministered AED Concentration Topiramate Concentration
Phenytoin
NC or 25% increasePlasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
48% decrease


Carbamazepine (CBZ)
NC
40% decrease
CBZ epoxideIs not administered but is an active metabolite of carbamazepine.
NC
NE
Valproic acid
11% decrease
14% decrease
Phenobarbital
NC
NE
Primidone
NC
NE
Lamotrigine
NC at TPM doses up to 400 mg/day
13% decrease


Table name:
AED Coadministered
AED Concentration
Topiramate 
Concentration

a= Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. b= Is not administered but is an active metabolite of carbamazepine. NC = Less than 10% change in plasma concentration. NE = Not Evaluated
Phenytoin
NC or 25% increasea
48% decrease
Carbamazepine (CBZ)
NC
40% decrease
CBZ epoxideb
NC
NE
Valproic acid
11% decrease
14% decrease
Phenobarbital
NC 
NE
Primidone
NC
NE
Lamotrigine
NC at TPM doses up to 400 mg/day
13% decrease



Table name:
Table 3Drugs that Can Increase the Risk of Bleeding
Drug  Class
Specific  Drugs
Anticoagulants 
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin 
Antiplatelet Agents 
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine 
Nonsteroidal Anti-Inflammatory Agents 
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac 
Serotonin Reuptake Inhibitors 
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone 


Table name:
Table 3: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction [See Clinical Pharmacology (12.3)]
Concomitant Drug Class:
Drug Name
Effect on Concentration of Etravirine or Concomitant Drug Clinical Comment
↑ = increase, ↓ = decrease, ↔ = no change
HIV-Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
efavirenzThe interaction between INTELENCE® and the drug was evaluated in a clinical study. All other drug interactions shown are predicted.
nevirapine
↓ etravirine Combining two NNRTIs has not been shown to be beneficial. Concomitant use of INTELENCE® with efavirenz or nevirapine may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of INTELENCE®. INTELENCE® and other NNRTIs should not be co-administered.
delavirdine ↑ etravirine Combining two NNRTIs has not been shown to be beneficial. INTELENCE® and delavirdine should not be co-administered.
rilpivirine ↓ rilpivirine
↔ etravirine
Combining two NNRTIs has not been shown to be beneficial. INTELENCE® and rilpivirine should not be coadministered.
HIV-Antiviral Agents: Protease Inhibitors (PIs)
atazanavir
(without ritonavir)
↓ atazanavir Concomitant use of INTELENCE® with atazanavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of atazanavir. INTELENCE® should not be co-administered with atazanavir without low-dose ritonavir.
atazanavir/ritonavir ↓ atazanavir
↑ etravirine
Concomitant use of INTELENCE® with atazanavir/ritonavir may cause a significant decrease in atazanavir Cmin and loss of therapeutic effect of atazanavir. In addition, the mean systemic exposure (AUC) of etravirine after co-administration of INTELENCE® with atazanavir/ritonavir is anticipated to be higher than the mean systemic exposure of etravirine observed in the Phase 3 trials after co-administration of INTELENCE® and darunavir/ritonavir (as part of the background regimen). INTELENCE® and atazanavir/ritonavir should not be co-administered.
darunavir/ritonavir ↓ etravirine The mean systemic exposure (AUC) of etravirine was reduced when INTELENCE® was co-administered with darunavir/ritonavir. Because all subjects in the Phase 3 trials received darunavir/ritonavir as part of the background regimen and etravirine exposures from these trials were determined to be safe and effective, INTELENCE® and darunavir/ritonavir can be co-administered without dose adjustments.
fosamprenavir
(without ritonavir)
↑ amprenavir Concomitant use of INTELENCE® with fosamprenavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of amprenavir. INTELENCE® should not be co-administered with fosamprenavir without low-dose ritonavir.
fosamprenavir/ritonavir ↑ amprenavir Due to a significant increase in the systemic exposure of amprenavir, the appropriate doses of the combination of INTELENCE® and fosamprenavir/ritonavir have not been established. INTELENCE® and fosamprenavir/ritonavir should not be co-administered.
indinavir
(without ritonavir)
↓ indinavir Concomitant use of INTELENCE® with indinavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of indinavir. INTELENCE® should not be co-administered with indinavir without low-dose ritonavir.
lopinavir/ritonavir ↓ etravirine The mean systemic exposure (AUC) of etravirine was reduced after co-administration of INTELENCE® with lopinavir/ritonavir (tablet). Because the reduction in the mean systemic exposures of etravirine in the presence of lopinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, INTELENCE® and lopinavir/ritonavir can be co-administered without dose adjustments.
nelfinavir
(without ritonavir)
↑ nelfinavir Concomitant use of INTELENCE® with nelfinavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of nelfinavir. INTELENCE® should not be co-administered with nelfinavir without low-dose ritonavir.
ritonavir ↓ etravirine Concomitant use of INTELENCE® with ritonavir 600 mg twice daily may cause a significant decrease in the plasma concentration of etravirine and loss of therapeutic effect of INTELENCE®. INTELENCE® and ritonavir 600 mg twice daily should not be co-administered.
saquinavir/ritonavir ↓ etravirine The mean systemic exposure (AUC) of etravirine was reduced when INTELENCE® was co-administered with saquinavir/ritonavir. Because the reduction in the mean systemic exposures of etravirine in the presence of saquinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, INTELENCE® and saquinavir/ritonavir can be co-administered without dose adjustments.
tipranavir/ritonavir ↓ etravirine Concomitant use of INTELENCE® with tipranavir/ritonavir may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of INTELENCE®. INTELENCE® and tipranavir/ritonavir should not be co-administered.
CCR5 Antagonists
maraviroc ↔ etravirine
↓ maraviroc
When INTELENCE® is co-administered with maraviroc in the absence of a potent CYP3A inhibitor (e.g., ritonavir boosted protease inhibitor), the recommended dose of maraviroc is 600 mg twice daily. No dose adjustment of INTELENCE® is needed.
maraviroc/darunavir/ritonavir ↔ etravirine
↑ maraviroc
When INTELENCE® is co-administered with maraviroc in the presence of a potent CYP3A inhibitor (e.g., ritonavir boosted protease inhibitor), the recommended dose of maraviroc is 150 mg twice daily. No dose adjustment of INTELENCE® is needed.
Other Agents
Antiarrhythmics:
digoxin
↔ etravirine
↑ digoxin
For patients who are initiating a combination of INTELENCE® and digoxin, the lowest dose of digoxin should initially be prescribed. For patients on a stable digoxin regimen and initiating INTELENCE®, no dose adjustment of either INTELENCE® or digoxin is needed. The serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect.
amiodarone,
bepridil,
disopyramide,
flecainide,
lidocaine (systemic),
mexiletine,
propafenone,
quinidine
↓ antiarrhythmics Concentrations of these antiarrhythmics may be decreased when co-administered with INTELENCE®. INTELENCE® and antiarrhythmics should be co-administered with caution. Drug concentration monitoring is recommended, if available.
Anticoagulants:
warfarin
↑ anticoagulants Warfarin concentrations may be increased when co-administered with INTELENCE®. The international normalized ratio (INR) should be monitored when warfarin is combined with INTELENCE®.
Anticonvulsants:
carbamazepine,
phenobarbital,
phenytoin
↓ etravirine Carbamazepine, phenobarbital and phenytoin are inducers of CYP450 enzymes. INTELENCE® should not be used in combination with carbamazepine, phenobarbital, or phenytoin as co-administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE®.
Antifungals:
fluconazole,
voriconazole
↑ etravirine
↔ fluconazole
↑ voriconazole
Co-administration of etravirine and fluconazole significantly increased etravirine exposures. The amount of safety data at these increased etravirine exposures is limited, therefore, etravirine and fluconazole should be co-administered with caution. No dose adjustment of INTELENCE® or fluconazole is needed.
Co-administration of etravirine and voriconazole significantly increased etravirine exposures. The amount of safety data at these increased etravirine exposures is limited, therefore, etravirine and voriconazole should be co-administered with caution. No dose adjustment of INTELENCE® or voriconazole is needed.
Antifungals:
itraconazole,
ketoconazole,
posaconazole
↑ etravirine
↓ itraconazole
↓ ketoconazole
↔ posaconazole
Posaconazole, a potent inhibitor of CYP3A4, may increase plasma concentrations of etravirine. Itraconazole and ketoconazole are potent inhibitors as well as substrates of CYP3A4. Concomitant systemic use of itraconazole or ketoconazole and INTELENCE® may increase plasma concentrations of etravirine. Simultaneously, plasma concentrations of itraconazole or ketoconazole may be decreased by INTELENCE®. Dose adjustments for itraconazole, ketoconazole or posaconazole may be necessary depending on the other co-administered drugs.
Antiinfectives:
clarithromycin
↑ etravirine
↓ clarithromycin
↑ 14-OH-clarithromycin
Clarithromycin exposure was decreased by INTELENCE®; however, concentrations of the active metabolite, 14-hydroxy-clarithromycin, were increased. Because 14-hydroxy-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered for the treatment of MAC.
Antimycobacterials:
rifampin,
rifapentine
↓ etravirine Rifampin and rifapentine are potent inducers of CYP450 enzymes. INTELENCE® should not be used with rifampin or rifapentine as co-administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE®.
Antimycobacterials:
rifabutin
↓ etravirine
↓ rifabutin
↓ 25-O-desacetylrifabutin
If INTELENCE® is NOT co-administered with a protease inhibitor/ritonavir, then rifabutin at a dose of 300 mg once daily is recommended.
If INTELENCE® is co-administered with darunavir/ritonavir, lopinavir/ritonavir or saquinavir/ritonavir, then rifabutin should not be co-administered due to the potential for significant reductions in etravirine exposure.
Benzodiazepines:
diazepam
↑ diazepam Concomitant use of INTELENCE® with diazepam may increase plasma concentrations of diazepam. A decrease in diazepam dose may be needed.
Corticosteroids:
dexamethasone (systemic)
↓ etravirine Systemic dexamethasone induces CYP3A and can decrease etravirine plasma concentrations. This may result in loss of therapeutic effect of INTELENCE®. Systemic dexamethasone should be used with caution or alternatives should be considered, particularly for long-term use.
Herbal Products:
St. John's wort (Hypericum perforatum)
↓ etravirine Concomitant use of INTELENCE® with products containing St. John's wort may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE®. INTELENCE® and products containing St. John's wort should not be co-administered.
HMG-CoA
Reductase Inhibitors:
atorvastatin

fluvastatin,
lovastatin,
pitavastatin,
pravastatin,
rosuvastatin,
simvastatin
↔ etravirine
↓ atorvastatin
↑ 2-OH-atorvastatin

↔ etravirine
↑ fluvastatin,
↓ lovastatin,
↑ pitavastatin,
↔ pravastatin,
↔ rosuvastatin,
↓ simvastatin
The combination of INTELENCE® and atorvastatin can be given without dose adjustments, however, the dose of atorvastatin may need to be altered based on clinical response.

No interaction between pravastatin, rosuvastatin and INTELENCE® is expected.

Lovastatin and simvastatin are CYP3A substrates and co-administration with INTELENCE® may result in lower plasma concentrations of the HMG-CoA reductase inhibitor. Fluvastatin and pitavastatin are metabolized by CYP2C9 and co-administration with INTELENCE® may result in higher plasma concentrations of the HMG-CoA reductase inhibitor. Dose adjustments for these HMG-CoA reductase inhibitors may be necessary.
Immunosuppressants:
cyclosporine,
sirolimus,
tacrolimus
↓ immunosuppressant INTELENCE® and systemic immunosuppressants should be co-administered with caution because plasma concentrations of cyclosporine, sirolimus, or tacrolimus may be affected.
Narcotic Analgesics/Treatment of Opioid Dependence:
buprenorphine, buprenorphine/naloxone,
methadone
↔ etravirine
↓ buprenorphine
↔ norbuprenorphine
↔ methadone
INTELENCE® and buprenorphine (or buprenorphine/naloxone) can be co-administered without dose adjustments, however, clinical monitoring for withdrawal symptoms is recommended as buprenorphine (or buprenorphine/naloxone) maintenance therapy may need to be adjusted in some patients.

INTELENCE® and methadone can be co-administered without dose adjustments, however, clinical monitoring for withdrawal symptoms is recommended as methadone maintenance therapy may need to be adjusted in some patients.
Phosphodiesterase Type 5
(PDE-5) Inhibitors:
sildenafil,
tadalafil,
vardenafil
↓ sildenafil
↓ N-desmethyl-sildenafil
INTELENCE® and sildenafil can be co-administered without dose adjustments, however, the dose of sildenafil may need to be altered based on clinical effect.
Platelet Aggregation Inhibitors:
clopidogrel
↓ clopidogrel (active) metabolite Activation of clopidogrel to its active metabolite may be decreased when clopidogrel is co-administered with INTELENCE®. Alternatives to clopidogrel should be considered.


Table name:
Interacting Agents Prescribing Recommendations 
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, gemfibrozil, cyclosporine,danazol Contraindicated with simvastatin 
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine  Do not exceed 20 mg simvastatin daily
Grapefruit juice Avoid grapefruit juice


Table name:
CYP2C19 or CYP3A4 Inducers
Clinical Impact: Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology (12.3)].
Intervention: St. John’s Wort, rifampin: Avoid concomitant use with omeprazole [see Warnings and Precautions (5.9)].

Ritonavir-containing products: see prescribing information for specific drugs.
CYP2C19 or CYP3A4 Inhibitors
Clinical Impact: Increased exposure of omeprazole [see Clinical Pharmacology (12.3)].
  Intervention: Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered.

See prescribing information for voriconazole.


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
↓= Decreased (induces lamotrigine gluronidation).
↑= Increased (inhibits lamotrigine gluronidation).
?= Conflicting data.
Concomitant Drug
Effect on Concentration of 
Lamotrigine or Concomitant Drug
Clinical Comment
Estrogen-containing oral 
contraceptive preparation containing 
30 mcg ethinylestradiol and 
150 mcg levonorgestrel 
↓ lamotrigine 



↓ levonorgestrel 
Decreased lamotrigine levels approximately 50%. 



Decrease in levonorgestrel component by 19%. 
Carbamazepine (CBZ) and CBZ epoxide 
↓ lamotrigine 



? CBZ epoxide 
Addition of carbamazepine decreases lamotrigine 
concentration approximately 40%. 


May increase CBZ epoxide levels 
Phenobarbital/Primidone 
↓ lamotrigine 
Decreased lamotrigine concentration approximately 40%. 
Phenytoin (PHT) 
↓ lamotrigine 
Decreased lamotrigine concentration approximately 40%. 
Rifampin 
↓ lamotrigine 
Decreased lamotrigine AUC approximately 40%. 
Valproate 
↑ lamotrigine  


? valproate 
Increased lamotrigine concentrations slightly
more than 2-fold. 

Decreased valproate concentrations an average of
25% over a 3-week period then stabilized in healthy
volunteers; no change in controlled clinical trials in
epilepsy patients. 


Table name:
Table 4: Clinically Significant Drug Interactions with OXYCONTIN
Inhibitors of CYP3A4 and CYP2D6
Clinical Impact: The concomitant use of OXYCONTIN and CYP3A4 inhibitors can increase the plasma concentration of oxycodone, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of OXYCONTIN and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of OXYCONTIN is achieved [see Warnings and Precautions (5.4)].
After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the oxycodone plasma concentration will decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to oxycodone.
Intervention: If concomitant use is necessary, consider dosage reduction of OXYCONTIN until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals.
If a CYP3A4 inhibitor is discontinued, consider increasing the OXYCONTIN dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
Examples Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)
CYP3A4 Inducers
Clinical Impact: The concomitant use of OXYCONTIN and CYP3A4 inducers can decrease the plasma concentration of oxycodone [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to oxycodone [see Warnings and Precautions (5.4)].
After stopping a CYP3A4 inducer, as the effects of the inducer decline, the oxycodone plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.
Intervention:

Examples:
If concomitant use is necessary, consider increasing the OXYCONTIN dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider OXYCONTIN dosage reduction and monitor for signs of respiratory depression.
Rifampin, carbamazepine, phenytoin
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Dosage and Administration (2.6), Warnings and Precautions (5.5)].
Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue OXYCONTIN if serotonin syndrome is suspected.
Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)].
Intervention: The use of OXYCONTIN is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples: phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact: May reduce the analgesic effect of OXYCONTIN and/or precipitate withdrawal symptoms.
Intervention: Avoid concomitant use.
Examples: butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact: Oxycodone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of OXYCONTIN and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when OXYCONTIN is used concomitantly with anticholinergic drugs.


Table name:
Interacting Drug Interaction
Drugs known to prolong QT interval (e.g., Class IA and Class III antiarrhythmic agents). Quinine sulfate prolongs QT interval, ECG abnormalities including QT prolongation and torsade de pointes. Avoid concomitant use (5.3).
Other antimalarials (e.g., halofantrine, mefloquine). ECG abnormalities including QT prolongation. Avoid concomitant use (5.3, 7.2).
CYP3A4 inducers or inhibitors Alteration in plasma quinine concentration. Monitor for lack of efficacy or increased adverse events of quinine (7.1).
CYP3A4 and CYP2D6 substrates Quinine is an inhibitor of CYP3A4 and CYP2D6. Monitor for lack of efficacy or increased adverse events of the coadministered drug (7.2).
Digoxin Increased digoxin plasma concentration (5.8, 7.1).


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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
 Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration  Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
 Drugs that may alter T 4 and T 3 metabolism
 Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


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Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, gemfibrozil, cyclosporine,danazol Contraindicated with simvastatin 
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine  Do not exceed 20 mg simvastatin daily
Grapefruit juice Avoid grapefruit juice


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Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓    lamotrigine     ↓    levonorgestrel Decreased lamotrigine concentrations approximately 50%.   Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide ↓    lamotrigine   ?   carbamazepine epoxide Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels.
Lopinavir/ritonavir ↓    lamotrigine Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir ↓    lamotrigine Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone ↓    lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin ↓    lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓    lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑    lamotrigine    ?   valproate   Increased lamotrigine concentrations slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.


Table name:
NA – Not available/reported
Digoxin concentrations increased greater than 50%
   Digoxin Serum   
Concentration Increase
   Digoxin AUC   
Increase
Recommendations
Amiodarone 70% NA Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring.
Captopril 58% 39%
Clarithromycin NA 70%
Dronedarone NA 150%
Gentamicin 129-212% NA
Erythromycin 100% NA
Itraconazole 80% NA
Nitrendipine 57% 15%
Propafenone NA 60-270%
Quinidine 100% NA
Ranolazine 50% NA
Ritonavir NA 86%
Tetracycline 100% NA
Verapamil 50-75% NA
Digoxin concentrations increased less than 50%
Atorvastatin 22% 15% Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring.
Carvedilol 16% 14%
Diltiazem 20% NA
Indomethacin 40% NA
Nefazodone 27% 15%
Nifedipine 45% NA
Propantheline 24% 24%
Quinine NA 33%
Saquinavir 27% 49%
Spironolactone      25% NA
Telmisartan 20-49% NA
Tolvaptan 30% NA
Trimethoprim 22-28% NA
Digoxin concentrations increased, but magnitude is unclear
Alprazolam, azithromycin, cyclosporine, diclofenac,
diphenoxylate, epoprostenol, esomeprazole, ibuprofen,
ketoconazole, lansoprazole, metformin, omeprazole,
rabeprazole,
Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin concentrations decreased
Acarbose, activated charcoal, albuterol, antacids, certain
cancer chemotherapy or radiation therapy, cholestyramine,
colestipol, extenatide, kaolin-pectin, meals high in bran,
metoclopramide, miglitol, neomycin, penicillamine,
phenytoin, rifampin, St. John’s Wort, sucralfate,
sulfasalazine
Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20-40% as necessary.
No significant Digoxin exposure changes
Please refer to section 12 for a complete list of drugs which     
were studied but reported no significant changes on digoxin exposure.
No additional actions are required.     


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Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s)
Recommendation
Comments
Tizanidine
Contraindicated
Concomitant administration of tizanidine and ciprofloxacin  is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)].
Theophylline
Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)
Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate. [See Warnings and Precautions (5.9).]
Drugs Known to Prolong QT Interval
Avoid Use
 
Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see  Warnings and Precautions (5.11) and Use in Specific Populations (8.5)].
Oral antidiabetic drugs
Use with caution Glucose-lowering effect potentiated
Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs. [See Adverse Reactions (6.1).]
Phenytoin
Use with caution Altered serum levels of phenytoin
(increased and decreased)
 
To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin with phenytoin.
Cyclosporine
Use with caution (transient elevations in serum creatinine)
Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs
Use with caution (Increase in anticoagulant effect)
The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate
Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels
Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole
Use with caution
Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin [see Warnings and Precautions (5.16)].
Clozapine
Use with caution
Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs
Use with caution
Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies in and postmarketing.
Sildenafil
Use with caution Two-fold increase in exposure
Monitor for sildenafil toxicity (see Clinical Pharmacology (12.3)].
Duloxetine
Avoid Use
Five-fold increase in duloxetine exposure
If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives
Use with caution Reduced clearance resulting in elevated levels and prolongation
of serum half-life
Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx® (didanosine) chewable/ buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)
Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2.4)].
Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid
Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)
Potentiation of ciprofloxacin toxicity may occur.


Table name:
Interacting Drug Interaction
Theophylline Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin Monitor phenytoin level (7)
Methotrexate Monitor for methotrexate toxicity (7)
Cyclosporine May increase serum creatinine. Monitor serum creatinine (7)
Multivalent cation-containing products including antacids, metal cations or didanosine Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin (7)


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Table 18. Summary of Effect of Co-administered Drugs on Exposure to Active Moiety (Risperidone + 9- Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Co-administered Drug  Dosing Schedule  Effect on Active Moeity (Risperidone + 9-Hydroxy-Risperidone (RatioChange relative to reference Risperidone Dose Recommendation 
  Co-administered Drug  Risperidone  AUC  Cmax   
Enzyme (CYP2D6) Inhibitors           
Fluoxetine  20 mg/day  2 or 3 twice daily  1.4  1.5  Re-evaluate dosing. Do not exceed 8 mg/day 
Paroxetine  10 mg/day  4 mg/day  1.3   - Re-evaluate dosing. Do not exceed 8 mg/day
  20 mg/day  4 mg/day  1.6   -   
  40 mg/day  4 mg/day  1.8   -  
Enzyme (CYP3A/PgP inducers) Inducers          
Carbamazepine 573 ± 168 mg/day  3 mg twice daily  0.51 0.55  Titrate dose upwards. Do not exceed twice the patient’s usual dose 
Enzyme (CYP3A) Inhibitors          
Ranitidine  150 mg twice daily  1 mg single dose  1.2  1.4  Dose adjustment not needed 
Cimetidine  400 mg twice daily  1 mg single dose  1.1  1.3  Dose adjustment not needed 
Erythromycin  500 mg four times daily  1 mg single dose  1.1  0.94  Dose adjustment not needed 
Other Drugs           
Amitriptyline  50 mg twice daily  3 mg twice daily  1.2  1.1  Dose adjustment not needed 


Table name:
Table 4 Other Potentially Significant Drug Interactions
Concomitant Drug Class or Food Noted or Anticipated Outcome Clinical Comment
HMG-Co A Reductase Inhibitors:
atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin
Pharmacokinetic and/or pharmacodynamic interaction: the addition of one drug to a stable long-term regimen of the other has resulted in myopathy and rhabdomyolysis (including a fatality) P-gp substrate; rhabdomyolysis has been reported Weigh the potential benefits and risks and carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during initial therapy; monitoring CPK (creatine phosphokinase) will not necessarily prevent the occurrence of severe myopathy.
Other Lipid-Lowering Drugs:
fibrates, gemfibrozil
Digitalis Glycosides:
digoxin


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant  Drug
Effect  on  Concentration  of  Lamotrigine  or 
Concomitant  Drug
Clinical  Comment 
↓= Decreased (induces lamotrigine gluronidation).
↑= Increased (inhibits lamotrigine glucuronidation).
?= Conflicting data.
Estrogen-containing oral 
contraceptive preparations 
containing 30 mcg ethinylestradiol 
and 150 mcg levonorgestrel
↓ lamotrigine




Decreased lamotrigine levels 
approximately 50%.




↓ levonorgestrel
Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and 
CBZ epoxide
↓ lamotrigine

Addition of carbamazepine decreases lamotrigine 
concentration approximately 40%.


? CBZ epoxide
May increase CBZ epoxide levels
Phenobarbital/Primidone
↓ lamotrigine
Decreased lamotrigine 
concentration approximately 40%.
Phenytoin (PHT)
↓ lamotrigine
Decreased lamotrigine 
concentration approximately 40%
Rifampin
↓ lamotrigine
Decreased lamotrigine AUC 
approximately 40%
Valproate
↑ lamotrigine

Increased lamotrigine concentrations slightly 
more than 2-fold.


? valproate
Decreased valproate concentrations an average of 
25% over a 3-week period then stabilized in healthy volunteers; 
no change in controlled clinical trials in epilepsy patients.



Table name:
I. Due to the competition of salicylate with other drugs for binding to serum albumin the following drug interactions may occur:
DRUG DESCRIPTION OF INTERACTION
Sulfonylureas Hypoglycemia potentiated.
Methotrexate Decreases tubular reabsorption; clinical toxicity from methotrexate can result.
Oral Anticoagulants Increased bleeding.
II. Drugs changing salicylate levels by altering renal tubular reabsorption:
DRUG DESCRIPTION OF INTERACTION
Corticosteroids Decreases plasma salicylate level; tapering doses of steroids may promote salicylism.
Acidifying Agents Increases plasma salicylate levels.
Alkanizing Agents Decreased plasma salicylate levels.
III. Drugs with complicated interactions with salicylates:
DRUG DESCRIPTION OF INTERACTION
Heparin Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients.
Pyrazinamide Inhibits pyrazinamide-induced hyperuricemia.
Uricosuric Agents Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited.
The following alterations of laboratory tests have been reported during salicylate therapy:
LABORATORY TESTS EFFECT OF SALICYLATES
Thyroid Function Decreased PBI; increased t3 uptake.
Urinary Sugar False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5g q.d.).
5-Hydroxyindole acetic acid False negative with fluorometric test.
Acetone ketone bodies False positive FeCI3 in Gerhardt reaction; red color persists with boiling.
17-OH corticosteroids False reduced values with >4.8g q.d. salicylate.
Vanilmandelic acid False reduced values.
Uric Acid May increase or decrease depending on dose.
Prothrombin Decreased levels; slightly increased prothrombin time.


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Drug Interactions Associated with Increased Risk of  Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice Avoid grapefruit juice


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Table IIl Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.*
  * Refer to PRECAUTIONS, Drug Interactions for information regarding table.

 albuterol, systemic and inhaled  hydrocortisone  nizatidine
 amoxicillin  isoflurane  norfloxacin
 ampicillin, with or without sulbactam  isoniazid  ofloxacin
 atenolol  isradipine  omeprazole
 azithromycin  influenza vaccine  prednisone, prednisolone
 caffeine, dietary ingestion  ketoconazole  ranitidine
 cefaclor  lomefloxacin  rifabutin
 co-trimoxazole  mebendazole  roxithromycin
 (trimethoprim and sulfamethoxazole) diltiazem  medroxyprogesterone  sorbitol
 dirithromycin  methylprednisolone  (purgative doses do not inhibit theophylline absorption)
 enflurane  metronidazole  sucralfate
 famotidine  metoprolol  terbutaline, systemic
 felodipine  nadolol  terfenadine
 finasteride  nifedipine  tetracycline
tocainide


Table name:
Drugs That Interfere with Hemostasis
Clinical Impact: Indomethacin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of indomethacin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of indomethacin with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ see Warnings and Precautions ( 5.11 )].
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ see Warnings and Precautions ( 5.2 ) ].
Intervention: Concomitant use of indomethacin capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions ( 5.11 )].Indomethacin is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: During concomitant use of indomethacin capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.During concomitant use of indomethacin capsules and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ see Warnings and Precautions ( 5.6 )].When these drugs are administered concomitantly, patients should be adequately hydrated.  Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.It has been reported that the addition of triamterene to a maintenance schedule of Indomethacin resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin and triamterene should not be administered together.Both indomethacin and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently [ see Warnings and Precautions ( 5.6 )].  
Intervention: Indomethacin and triamterene should not be administered together. During concomitant use of indomethacin capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects. Be aware that indomethacin and potassium-sparing diuretics may both be associated with increased serum potassium levels. [ see Warnings and Precautions ( 5.6 )].  
Digoxin  
Clinical Impact: The concomitant use of indomethacin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.  
Intervention: During concomitant use of indomethacin capsules and digoxin, monitor serum digoxin levels.  
Lithium  
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.  
Intervention: During concomitant use of indomethacin capsules and lithium, monitor patients for signs of lithium toxicity.  
Methotrexate  
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).  
Intervention: During concomitant use of indomethacin capsules and methotrexate, monitor patients for methotrexate toxicity.  
Cyclosporine  
Clinical Impact: Concomitant use of indomethacin capsules and cyclosporine may increase cyclosporine's nephrotoxicity.  
Intervention: During concomitant use of indomethacin capsules and cyclosporine, monitor patients for signs of worsening renal function.  
NSAIDs and Salicylates  
Clinical Impact: Concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ see Warnings and Precautions ( 5.2 )]. Combined use with diflunisal may be particularly hazardous because diflunisal causes significantly higher plasma levels of indomethacin [see Clinical Pharmacology ( 12.3 )].In some patients, combined use of indomethacin and diflunisal has been associated with fatal gastrointestinal hemorrhage.  
Intervention: The concomitant use of indomethacin with other NSAIDs or salicylates, especially diflunisal, is not recommended.  
Pemetrexed  
Clinical Impact: Concomitant use of indomethacin capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).  
Intervention: During concomitant use of indomethacin capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.  
Probenecid  
Clinical Impact: When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased.  
Intervention: During the concomitant use of indomethacin and probenecid, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect.  When increases in the dose of indomethacin are made, they should be made carefully and in small increments.  


Table name:
Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.*
*Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol,  systemic and inhaled hydrocortisone nizatidine      
amoxicillin isoflurane norfloxacin
ampicillin,   with or without sulbactam isoniazid ofloxacin
atenolol isradipine omeprazole
azithromycin influenza vaccine prednisone, prednisolone
caffeine,   dietary ingestion ketoconazole ranitidine
cefaclor lomefloxacin rifabutin        
co-trimoxazole  (trimethoprim and sulfamethoxazole) mebendazole roxithromycin  
diltiazem medroxyprogesterone        sorbitol (purgative doses do not inhibit
dirithromycin methylprednisolone                        theophylline absorption)
enflurane metronidazole sucralfate
famotidine metoprolol terbutaline, systemic
felodipine nadolol terfenadine
finasteride nifedipine tetracycline
tocainide


Table name:
Drugs That Interfere with Hemostasis
  Clinical Impact: Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of celecoxib capsules with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ see Warnings and Precautions (5.11) ].
Aspirin
   Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ see Warnings and Precautions (5.2) ]. In two studies in healthy volunteers, and in patients with osteoarthritis and established heart disease respectively, celecoxib (200-400 mg daily) has demonstrated a lack of interference with the cardioprotective antiplatelet effect of aspirin (100-325 mg).
Intervention: Concomitant use of celecoxib capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions (5.11) ]. Celecoxib capsules are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
  Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
   Intervention: During concomitant use of celecoxib capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of celecoxib capsules and ACE-inhibitors or ARBs in patients who are elderly, volume- depleted, or have impaired renal function, monitor for signs of worsening renal function [ see Warnings and Precautions (5.6) ]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of celecoxib capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ see Warnings and Precautions (5.6) ].
Digoxin
Clinical Impact: The concomitant use of celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of celecoxib capsules and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of celecoxib capsules and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Celecoxib capsules have no effect on methotrexate pharmacokinetics.
Intervention: During concomitant use of celecoxib capsules and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of celecoxib capsules and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of celecoxib capsules and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ see Warnings and Precautions (5.2) ].
Intervention: The concomitant use of celecoxib with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of celecoxib capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of celecoxib capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.
NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.
In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
CYP2C9 Inhibitors or inducers
Clinical Impact: Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Co­-administration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of celecoxib.
Intervention Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers [ see Clinical Pharmacology (12.3) ].
CYP2D6 substrates
Clinical Impact: In vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6 (e.g. atomoxetine), and celecoxib may enhance the exposure and toxicity of these drugs.
Intervention Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2D6 substrates [ see Clinical Pharmacology (12.3) ].
Corticosteroids
Clinical Impact: Concomitant use of corticosteroids with celecoxib capsules may increase the risk of GI ulceration or bleeding.
Intervention Monitor patients with concomitant use of celecoxib capsules with corticosteroids for signs of bleeding [see Warnings and Precautions (5.2)].


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
CYP2C19 or CYP3A4 Inducers
Clinical Impact: Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology (12.3)].
Intervention: St. John’s Wort, rifampin: Avoid concomitant use with omeprazole [see Warnings and Precautions (5.9)].

Ritonavir-containing products: see prescribing information for specific drugs.
CYP2C19 or CYP3A4 Inhibitors
Clinical Impact: Increased exposure of omeprazole [see Clinical Pharmacology (12.3)].
  Intervention: Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered.

See prescribing information for voriconazole.


Table name:
LABORATORY TESTS EFFECT OF SALICYLATES
Thyroid Function Decreased PBI; increased T3 uptake.
Urinary Sugar False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5g q.d.).
5-Hydroxyindole acetic acid False negative with fluorometric test.
Acetone, ketone bodies False positive FeCl3 in Gerhardt reaction; red color persists with boiling.
17-OH corticosteroids False reduced values with >4.8g q.d. salicylate.
Vanilmandelic acid False reduced values.
Uric acid May increase or decrease depending on dose.
Prothrombin Decreased levels; slightly increased prothrombin time.


Table name:
Bleeding times
Clinical Impact: Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention: This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact: The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention: Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact: Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention: This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.


Table name:
Name of the
Concomitant Drug
Change in the Concentration of Ganciclovir or
Concomitant Drug

Clinical Comment
Zidovudine
↓ Ganciclovir
↑ Zidovudine
Zidovudine and valganciclovir tablets each have the potential to cause neutropenia and anemia
Probenicid
↑ Ganciclovir
Patients taking probenicid and valganciclovir tablets should be monitored for evidence of ganciclovir toxicity
Mycophenolate  Mofetil
(MMF)
↔  Ganciclovir (in patients with normal renal function)
↔ MMF (in patients with normal renal function)
Patients with renal impairment should be monitored carefully as levels of MMF metabolites and ganciclovir may increase
Didanosine
↓ Ganciclovir
↑ Didanosine
Patients should be closely monitored for didanosine toxicity


Table name:
Table 2: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 5 mg in BPH patients on stable alpha-blocker therapy (Study 1)
Alpha-Blocker Simultaneous dosing of Vardenafil 5 mg
and Alpha-Blocker,
Placebo-Subtracted
Dosing of Vardenafil 5 mg
and Alpha-Blocker
Separated by 6 Hours,
Placebo-Subtracted
Terazosin
5 or 10 mg daily
Standing SBP -3 (-6.7, 0.1) -4 (-7.4, -0.5)
Supine SBP -4 (-6.7, -0.5) -4 (-7.1, -0.7)
Tamsulosin
0.4 mg daily
Standing SBP
Supine SBP
-6 (-9.9, -2.1)
-4 (-7.0, -0.8)
-4 (-8.3, -0.5)
-5 (-7.9, -1.7)


Table name:
CONCOMITANT  DRUG CLINICAL EFFECT(S)        
Amphetamines, cocaine, other sympathomimetic agents Additive hypertension, tachycardia, possibly cardiotoxicity
Atropine, scopolamine, antihistamines, other anticholinergic agents Additive or super-additive tachycardia, drowsiness
Amitriptyline, amoxapine, desipramine, other tricyclic antidepressants Additive tachycardia, hypertension, drowsiness
Barbiturates, benzodiazepines, ethanol, lithium, opioids, buspirone, antihistamines, muscle relaxants, other CNS depressants Additive drowsiness and CNS depression
Disulfiram A reversible hypomanic reaction was reported in a 28 y/o man who smoked marijuana; confirmed by dechallenge and rechallenge
Fluoxetine A 21 y/o female with depression and bulimia receiving 20 mg/day fluoxetine X 4 wks became hypomanic after smoking marijuana; symptoms resolved after 4 days
Antipyrine, barbiturates Decreased clearance of these agents,presumably via competitive inhibition of metabolism
Theophylline Increased theophylline metabolism reported with smoking of marijuana; effect similar to that following smoking tobacco


Table name:
Table 8: Effect of Voriconazole on Pharmacokinetics of Other Drugs [see Clinical Pharmacology (12.3)]
Drug/Drug Class
(Mechanism of Interaction by Voriconazole)
Drug Plasma Exposure
(Cmax and AUCτ)
Recommendations for Drug Dosage Adjustment/Comments
SirolimusResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects
(CYP3A4 Inhibition)
Significantly Increased Contraindicated
Rifabutin
(CYP3A4 Inhibition)
Significantly Increased Contraindicated
Efavirenz (400 mg q24h)Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects
(CYP3A4 Inhibition)
Significantly Increased Contraindicated
Efavirenz (300 mg q24h)
(CYP3A4 Inhibition)
Slight Increase in AUCτ When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)(CYP3A4 Inhibition) No Significant Effect of Voriconazole on Ritonavir Cmax or AUCτ Contraindicated because of significant reduction of voriconazole Cmax and AUCτ
     
Low-dose Ritonavir (100 mg q12h) Slight Decrease in Ritonavir Cmax and AUCτ Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole Cmax and AUCτ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine
(CYP3A4 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids
(CYP450 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Contraindicated
Cyclosporine
(CYP3A4 Inhibition)
AUCτ Significantly Increased; No Significant Effect on Cmax When initiating therapy with VFEND in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When VFEND is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
MethadoneResults based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for 4 days voriconazole to subjects receiving a methadone maintenance dose (30–100 mg q24h) (CYP3A4 Inhibition) Increased Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl (CYP3A4 Inhibition)
Increased Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7)]
Alfentanil (CYP3A4 Inhibition) Significantly Increased Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with VFEND. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [see Drug Interactions (7)].
Oxycodone (CYP3A4 Inhibition) Significantly Increased Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7)].
NSAIDsNon-Steroidal Anti-Inflammatory Drug including. ibuprofen and diclofenac
(CYP2C9 Inhibition)
Increased Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed [see Drug Interactions (7)].
Tacrolimus
(CYP3A4 Inhibition)
Significantly Increased When initiating therapy with VFEND in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When VFEND is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin
(CYP2C9 Inhibition)
Significantly Increased Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition) Increased Monitoring for adverse events related to oral contraceptives is recommended during coadministration.
Warfarin
(CYP2C9 Inhibition)
Prothrombin Time Significantly Increased Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed.
Omeprazole
(CYP2C19/3A4 Inhibition)
Significantly Increased When initiating therapy with VFEND in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors
(CYP3A4 Inhibition)
In Vivo Studies Showed No Significant Effects on Indinavir Exposure No dosage adjustment for indinavir when coadministered with VFEND
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism
(Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors
(CYP3A4 Inhibition)
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs
(Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity related to NNRTI
Benzodiazepines
(CYP3A4 Inhibition)
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism
(Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.
HMG-CoA Reductase Inhibitors (Statins)
(CYP3A4 Inhibition)
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism
(Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers
(CYP3A4 Inhibition)
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism
(Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics
(CYP2C9 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids
(CYP3A4 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed.
Everolimus
(CYP3A4 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Concomitant administration of voriconazole and everolimus is not recommended.


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium ( 2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( 7.2)
Antidiabetic agents Carefully monitor blood glucose ( 5.12, 7.3)


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
  Interacting Drug  Interaction
 Multivalent cation-containing products including antacids, metal cations or didanosine  Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
 Warfarin  Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
 Antidiabetic agents  Carefully monitor blood glucose (5.11, 7.3)


Table name:
Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death.
Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.4)].
Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.


Table name:
Table 7: Summary of AED Interactions with Oxcarbazepine
AED Coadministered Dose of AED (mg/day) Oxcarbazepine Dose (mg/day) Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval) Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine
400 to 2,000
900
ncnc denotes a mean change of less than 10%
40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital
100 to 150
600 to 1,800
14% increase [CI: 2% increase, 24% increase]
25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin
250 to 500
600 to 1,800 >1,200 to 2,400
nc Pediatrics
up to 40% increaseMean increase in adults at high oxcarbazepine doses [CI: 12% increase, 60% increase]
30% decrease [CI: 3% decrease, 48% decrease]
Valproic acid
400 to 2,800
600 to 1,800
nc
18% decrease [CI: 13% decrease, 40% decrease]


Table name: Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of Celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.During concomitant use of celecoxib and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of celecoxib and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6) ]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Table 3: Clinically Significant Drug Interactions with Celecoxib
 Drugs That Interfere with Hemostasis
Clinical Impact:
Intervention:
Monitor patients with concomitant use of celecoxib with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11) ].
 Aspirin
Clinical Impact:
Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2) ].
In two studies in healthy volunteers, and in patients with osteoarthritis and established heart disease respectively, celecoxib (200 to 400 mg daily) has demonstrated a lack of interference with the cardioprotective antiplatelet effect of aspirin (100 to 325 mg).
Intervention:
Concomitant use of celecoxib and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11) ].
Celecoxib is not a substitute for low dose aspirin for cardiovascular protection.
 ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:
Intervention:
 Diuretics
Clinical Impact:
Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:
During concomitant use of celecoxib with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6) ].
 Digoxin
Clinical Impact:
The concomitant use of Celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:
During concomitant use of celecoxib and digoxin, monitor serum digoxin levels.
 Lithium
Clinical Impact:
NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:
During concomitant use of celecoxib and lithium, monitor patients for signs of lithium toxicity.
 Methotrexate
Clinical Impact:
Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Celecoxib has no effect on methotrexate pharmacokinetics.
Intervention:
During concomitant use of celecoxib and methotrexate, monitor patients for methotrexate toxicity.
 Cyclosporine
Clinical Impact:
Concomitant use of celecoxib and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:
During concomitant use of celecoxib and cyclosporine, monitor patients for signs of worsening renal function.
 NSAIDs and Salicylates
Clinical Impact:
Concomitant use of Celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2) ].
Intervention:
The concomitant use of Celecoxib with other NSAIDs or salicylates is not recommended.
 Pemetrexed
Clinical Impact:
Concomitant use of celecoxib and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:
During concomitant use of celecoxib and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.
NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.
In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
 CYP2C9 Inhibitors or inducers
Clinical Impact:
Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Co‑-administration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of celecoxib.
Intervention
Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers. [see Clinical Pharmacology (12.3) ].
 CYP2D6 substrates
Clinical Impact:
In vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6 (e.g. atomoxetine), and celecoxib may enhance the exposure and toxicity of these drugs.
Intervention
Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2D6 substrates. [see Clinical Pharmacology (12.3) ].
 Corticosteroids
Clinical Impact:
Concomitant use of corticosteroids with celecoxib may increase the risk of GI ulceration or bleeding.
Intervention
Monitor patients with concomitant use of celecoxib with corticosteroids for signs of bleeding [see Warnings and Precautions (5.2) ].


Table name:
Interacting Drug Interaction
Theophylline Serious and fatal reactions. Avoid concomitant use. Monitor serum level ( 7)
Warfarin Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding ( 7)
Antidiabetic agents Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose ( 7)
Phenytoin Monitor phenytoin level ( 7)
Methotrexate Monitor for methotrexate toxicity ( 7)
Cyclosporine May increase serum creatinine. Monitor serum creatinine ( 7)
Multivalent cation-containing products including antacids, metal cations or didanosine Decreased Ciprofloxacin Tablets, USP absorption. Take 2 hours before or 6 hours after Ciprofloxacin Tablets, USP ( 7)


Table name:
Table 3: Clinically Relevant Interactions Affecting Drugs Co-Administered with Omeprazole and Interaction with Diagnostics
Antiretrovirals
Clinical Impact:
The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known.
 
Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology (12.3)]. Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see Clinical Pharmacology (12.3)]. There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole.
Intervention:
Rilpivirine-containing products: Concomitant use with omeprazole is contraindicated [see Contraindications (4) ].
 
Atazanavir: Avoid concomitant use with omeprazole. See prescribing information for atazanavir for dosing information.
 
Nelfinavir: Avoid concomitant use with omeprazole. See prescribing information for nelfinavir.
 
Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities.
 
Other antiretrovirals: See prescribing information for specific antiretroviral drugs.
Warfarin
Clinical Impact:
Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
         Intervention:
Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range.
Methotrexate
Clinical Impact:
Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions (5.11) ].
Intervention:
A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate.
CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam)
Clopidogrel
Clinical Impact:
Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology (12.3) ].
There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel.
        Intervention:
Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy [see Warnings and Precautions (5.6) ].
Citalopram
Clinical Impact:
Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology (12.3) ].
         Intervention:
Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.
Cilostazol
Clinical Impact:
Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology (12.3) ].
          Intervention:
Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.
Phenytoin
Clinical Impact:
Potential for increased exposure of phenytoin.
         Intervention:
Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin.
Diazepam
Clinical Impact:
Increased exposure of diazepam [see Clinical Pharmacology (12.3) ].
Intervention:
Monitor patients for increased sedation and reduce the dose of diazepam as needed.
Digoxin
Clinical Impact:
Potential for increased exposure of digoxin [see Clinical Pharmacology (12.3) ].
Intervention:
Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)
Clinical Impact:
Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
Intervention:
Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF [see Clinical Pharmacology (12.3) ].
 
See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact:
Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions.
Intervention:
See Contraindications Warnings and Precautions   in prescribing information for clarithromycin.
 
See  Drug Interactions   in prescribing information for amoxicillin.
Tacrolimus
Clinical Impact:
Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.
Intervention:
Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact:
Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions (5.10) , Clinical Pharmacology (12.2) ].
Intervention:
Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
Interaction with Secretin Stimulation Test
Clinical Impact:
Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention:
Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology (12.2)].
False Positive Urine Tests for THC
Clinical Impact:
There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.
Intervention:
An alternative confirmatory method should be considered to verify positive results.
Other
Clinical Impact:
There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram).
Intervention:
Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole.


Table name:
Table 3 Clinically Significant Drug Interactions with Meloxicam
Drugs  that  Interfere  with  Hemostasis 
Clinical  Impact
Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. 
Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. 
Intervention

Monitor patients with concomitant use of Meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin 
Clinical  Impact
Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].
Intervention

Concomitant use of Meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. Meloxicam is not a substitute for low dose aspirin for cardiovascular protection.
ACE  Inhibitors Angiotensin  Receptor  Blockers or  Beta - Blockers 
Clinical  Impact
NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). 
In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, coadministration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. 
Intervention

During concomitant use of Meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.  During concomitant use of Meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics 
Clinical  Impact
Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. 
Intervention

During concomitant use of Meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Lithium 
Clinical  Impact
NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [see Clinical Pharmacology (12.3)].
Intervention

During concomitant use of Meloxicam and lithium, monitor patients for signs of lithium toxicity. 
Methotrexate 
Clinical  Impact
Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). 
Intervention

During concomitant use of Meloxicam and methotrexate, monitor patients for methotrexate toxicity. 
Cyclosporine 
Clinical  Impact
Concomitant use of Meloxicam and cyclosporine may increase cyclosporine's nephrotoxicity. 
Intervention

During concomitant use of Meloxicam and cyclosporine, monitor patients for signs of worsening renal function. 
NSAIDs  and  Salicylates 
Clinical  Impact
Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention

The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended. 
Pemetrexed 
Clinical  Impact
Concomitant use of Meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). 
Intervention

During concomitant use of Meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. 

Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. 

In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended. 


Table name:
Table 18. Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
*Change relative to reference
Coadministered Drug

Dosing Schedule
Effect on Active Moiety
(Risperidone + 9- Hydroxy-
Risperidone (Ratio*)
Risperidone Dose
Recommendation
Coadministered Drug
Risperidone
AUC
Cmax
Enzyme (CYP2D6) inhibitors




Fluoxetine
20 mg/day
2 or 3 mg twice daily
1.4
1.5

Re-evaluate dosing.
Do not exceed 8 mg/day
Paroxetine
10 mg/day
4 mg/day
1.3
-

Re-evaluate dosing.
Do not exceed 8 mg/day
20 mg/day
4 mg/day
1.6
-
40 mg/day
4 mg/day
1.8
-
Enzyme (CYP3A/ PgP inducers) Inducers





Carbamazepine
573 ± 168 mg/day

3 mg twice daily

0.51

0.55


Titrate dose upwards.
Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) inhibitors





Ranitidine
150 mg twice daily
1 mg single dose
1.2
1.4
Dose adjustment not needed
Cimetidine
400 mg twice daily
1 mg single dose
1.1
1.3
Dose adjustment not needed
Erythromycin
500 mg four times daily
1 mg single dose
1.1
0.94
Dose adjustment not needed
Other Drugs





Amitriptyline
50 mg twice daily
3 mg twice daily
1.2
1.1
Dose adjustment not Needed


Table name:
Table 7 Summary of AED Interactions with Oxcarbazepine
AED Coadministered Dose of AED (mg/day) Oxcarbazepine Dose (mg/day) Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval) Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine 400-2000 900 ncnc denotes a mean change of less than 10% 40% decrease [CI: 17% decrease,57% decrease]
Phenobarbital 100-150 600-1800 14% increase[CI: 2% increase, 24% increase] 25% decrease [CI: 12% decrease,51% decrease]
Phenytoin 250-500 600-1800>1200-2400 nc up to 40% increase [CI: 12% increase,60% increase] 30% decrease [CI: 3% decrease,48% decrease]
Valproic acid 400-2800 600-1800 nc 18% decrease [CI: 13% decrease,40% decrease]


Table name:
Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Table 18 Summary of Effect of Co-administered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
  Co-administered Drug   Dosing Schedule   Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*)   Risperidone Dose Recommendation
    Co-administered Drug   Risperidone   AUC   Cmax  
 Enzyme (CYP2D6)Inhibitors          
 Fluoxetine  20 mg/day  2 or 3 mg twice daily  1.4  1.5  Re-evaluate dosing. Do not exceed 8 mg/day
 Paroxetine  10 mg/day  4 mg/day  1.3  -  
   20 mg/day  4 mg/day  1.6  -  
   40 mg/day  4 mg/day  1.8  -  Re-evaluate dosing. Do not exceed 8 mg/day
 Enzyme (CYP3A/PgP inducers)Inducers          
 Carbamazepine  573 ± 168 mg/day  3 mg twice daily  0.51  0.55  Titrate dose upwards. Do not exceed twice the patient’s usual dose
 Enzyme (CYP3A)Inhibitors          
 Ranitidine  150 mg twice daily  1 mg single dose  1.2  1.4  Dose adjustment not needed
 Cimetidine  400 mg twice daily  1 mg single dose  1.1  1.3  Dose adjustment not needed
 Erythromycin  500 mg four times daily  1 mg single dose  1.1  0.94  Dose adjustment not needed
           
 Other Drugs          
 Amitriptyline  50 mg twice daily  3 mg twice daily  1.2  1.1  Dose adjustment not needed


Table name:
Figure 1: Effect of interacting drugs on the pharmacokinetics of venlafaxine and active metabolite O-desmethylvenlafaxine (ODV).


Table name:
CONCOMITANT DRUG CLINICAL EFFECT(S)
Amphetamines, cocaine, other sympathomimetic agents Additive hypertension, tachycardia, possibly cardiotoxicity
Atropine, scopolamine, antihistamines, other anticholinergic agents Additive or super-additive tachycardia, drowsiness
Amitriptyline, amoxapine, desipramine, other tricyclic antidepressants Additive tachycardia, hypertension, drowsiness
Barbiturates, benzodiazepines, ethanol, lithium, opioids, buspirone, antihistamines, muscle relaxants, other CNS depressants Additive drowsiness and CNS depression
Disulfiram A reversible hypomanic reaction was reported in a 28 y/o man who smoked marijuana; confirmed by dechallenge and rechallenge
Fluoxetine A 21 y/o female with depression and bulimia receiving 20 mg/day fluoxetine X 4 wks became hypomanic after smoking marijuana; symptoms resolved after 4 days
Antipyrine, barbiturates Decreased clearance of these agents, presumably via competitive inhibition of metabolism
Theophylline Increased theophylline metabolism reported with smoking of marijuana; effect similar to that following smoking tobacco


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Table 9 Established and Other Potentially Significant Drug Interactions With Ganciclovir
Name of the Concomitant Drug Change in the Concentration of Ganciclovir or Concomitant Drug Clinical Comment
 Zidovudine  ↓ Ganciclovir
↑ Zidovudine
 Zidovudine and valganciclovir each have the potential to cause neutropenia and anemia
 Probenecid  ↑ Ganciclovir  Patients taking probenecid and valganciclovir should be monitored for evidence of ganciclovir toxicity
 Mycophenolate Mofetil (MMF)  ↔ Ganciclovir (in patients with normal renal function)
↔ MMF (in patients with normal renal function)
 Patients with renal impairment should be monitored carefully as levels of MMF metabolites and ganciclovir may increase
 Didanosine  ↓ Ganciclovir
 ↑ Didanosine
 Patients should be closely monitored for didanosine toxicity


Table name:
Table 7: Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology (12.3)]
Drug/Drug Class
(Mechanism of Interaction by the Drug)
Voriconazole Plasma Exposure
(Cmax and AUCτ after 200 mg q12h)
Recommendations for Voriconazole Dosage Adjustment/Comments
RifampinResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg q12h voriconazole to healthy subjects and Rifabutin
(CYP450 Induction)
Significantly Reduced Contraindicated
Efavirenz (400 mg q24h)Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects
(CYP450 Induction)
Significantly Reduced Contraindicated
 
Efavirenz (300 mg q24h)
(CYP450 Induction)
Slight Decrease in AUC τ When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h) (CYP450 Induction) Significantly Reduced Contraindicated
 
Low-dose Ritonavir (100 mg q12h) (CYP450 Induction)
Reduced Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Carbamazepine
(CYP450 Induction)
Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction Contraindicated
Long Acting Barbiturates
(CYP450 Induction)
Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction Contraindicated
Phenytoin
(CYP450 Induction)
Significantly Reduced Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg)
St. John's Wort
(CYP450 inducer; P-gp inducer)
Significantly Reduced Contraindicated
Oral Contraceptives
containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)
Increased Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole (CYP2C9, CYP2C19 and CYP3A4 Inhibition) Significantly Increased Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole.
Other HIV Protease Inhibitors
(CYP3A4 Inhibition)
In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir
 
In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors
(CYP3A4 Inhibition or CYP450 Induction)
In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to voriconazole
 
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs
(Decreased Plasma Exposure)
Careful assessment of voriconazole effectiveness


Table name:
Drugs That Interfere with Hemostasis
Clinical Impact: • Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of naproxen or naproxen sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: Concomitant use of naproxen or naproxen sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen or naproxen sodium is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE-inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: • During concomitant use of naproxen or naproxen sodium and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of naproxen or naproxen sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen or naproxen sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact: The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of naproxen or naproxen sodium and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen or naproxen sodium and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of naproxen or naproxen sodium and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of naproxen or naproxen sodium and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of naproxen or naproxen sodium and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of naproxen or naproxen sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of naproxen or naproxen sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact: Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention: Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen or naproxen sodium is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed release tablets are not recommended.
Cholestyramine
Clinical Impact: Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention: Concomitant administration of cholestyramine with naproxen or naproxen sodium is not recommended.
Probenecid
Clinical Impact: Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention: Patients simultaneously receiving naproxen or naproxen sodium and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact: Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention: Patients simultaneously receiving naproxen or naproxen sodium and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.


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CONCOMITANT DRUG CLINICAL EFFECT(S)
Amphetamines, cocaine, other sympathomimetic agents Additive hypertension, tachycardia, possibly cardiotoxicity
Atropine, scopolamine, antihistamines, other anticholinergic agents Additive or super-additive tachycardia, drowsiness
Amitriptyline, amoxapine, desipramine, other tricyclic antidepressants Additive tachycardia, hypertension, drowsiness
Barbiturates, benzodiazepines, ethanol, lithium, opioids, buspirone, antihistamines, muscle relaxants, other CNS depressants Additive drowsiness and CNS depression
Disulfiram A reversible hypomanic reaction was reported in a 28 y/o man who smoked marijuana; confirmed by dechallenge and rechallenge
Fluoxetine A 21 y/o female with depression and bulimia receiving 20 mg/day fluoxetine X 4 wks became hypomanic after smoking marijuana; symptoms resolved after 4 days
Antipyrine, barbiturates Decreased clearance of these agents, presumably via competitive inhibition of metabolism
Theophylline Increased theophylline metabolism reported with smoking of marijuana; effect similar to that following smoking tobacco
Opioids Cross-tolerance and mutual potentiation
Naltrexone Oral THC effects were enhanced by opioid receptor blockade.
Alcohol Increase in the positive subjective mood effects of smoked marijuana


Table name:
 NA – Not available/reported
  Digoxin concentrations increased greater than 50%
      Digoxin Serum   
Concentration Increase
    Digoxin AUC   
Increase
  Recommendations
 Amiodarone  70%  NA  Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring.
 Captopril  58%  39%
 Clarithromycin  NA  70%
 Dronedarone  NA  150%
 Gentamicin  129-212%  NA
 Erythromycin  100%  NA
 Itraconazole  80%  NA
 Nitrendipine  57%  15%
 Propafenone  NA  60-270%
 Quinidine  100%  NA
 Ranolazine  50%  NA
 Ritonavir  NA  86%
 Tetracycline  100%  NA
 Verapamil  50-75%  NA
  Digoxin concentrations increased less than 50%
 Atorvastatin  22%  15%  Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring.
 Carvedilol  16%  14%
 Diltiazem  20%  NA
 Indomethacin  40%  NA
 Nefazodone  27%  15%
 Nifedipine  45%  NA
 Propantheline  24%  24%
 Quinine  NA  33%
 Saquinavir  27%  49%
 Spironolactone       25%  NA
 Telmisartan  20-49%  NA
 Tolvaptan  30%  NA
 Trimethoprim  22-28%  NA
  Digoxin concentrations increased, but magnitude is unclear
 Alprazolam, azithromycin, cyclosporine, diclofenac,
diphenoxylate, epoprostenol, esomeprazole, ibuprofen,
ketoconazole, lansoprazole, metformin, omeprazole,
rabeprazole,
 Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
  Digoxin concentrations decreased
 Acarbose, activated charcoal, albuterol, antacids, certain
cancer chemotherapy or radiation therapy, cholestyramine,
colestipol, extenatide, kaolin-pectin, meals high in bran,
metoclopramide, miglitol, neomycin, penicillamine,
phenytoin, rifampin, St. John’s Wort, sucralfate,
sulfasalazine
 Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20-40% as necessary.
  No significant Digoxin exposure changes
 Please refer to section 12 for a complete list of drugs which     
were studied but reported no significant changes on digoxin exposure.
 No additional actions are required.     


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Table 6: Clinically Significant Drug Interactions with BASAGLAR
Drugs That May Increase the Risk of Hypoglycemia
Drugs: Antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, propoxyphene, salicylates, somatostatin analogs (e.g., octreotide), and sulfonamide antibiotics.
Intervention: Dose reductions and increased frequency of glucose monitoring may be required when BASAGLAR is co-administered with these drugs.
Drugs That May Decrease the Blood Glucose Lowering Effect of BASAGLAR
Drugs: Atypical antipsychotics (e.g., olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones
Intervention: Dose increases and increased frequency of glucose monitoring may be required when BASAGLAR is co-administered with these drugs.
Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of BASAGLAR
Drugs: Alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia.
Intervention: Dose adjustment and increased frequency of glucose monitoring may be required when BASAGLAR is co-administered with these drugs.
Drugs That May Blunt Signs and Symptoms of Hypoglycemia
Drugs: beta-blockers, clonidine, guanethidine, and reserpine
Intervention: Increased frequency of glucose monitoring may be required when BASAGLAR is co-administered with these drugs.


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Table 4: Clinically Significant Drug Interactions with OXYCONTIN
Inhibitors of CYP3A4 and CYP2D6
Clinical Impact: The concomitant use of OXYCONTIN and CYP3A4 inhibitors can increase the plasma concentration of oxycodone, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of OXYCONTIN and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of OXYCONTIN is achieved [see Warnings and Precautions (5.4)].
After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the oxycodone plasma concentration will decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to oxycodone.
Intervention: If concomitant use is necessary, consider dosage reduction of OXYCONTIN until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals.
If a CYP3A4 inhibitor is discontinued, consider increasing the OXYCONTIN dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
Examples Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)
CYP3A4 Inducers
Clinical Impact: The concomitant use of OXYCONTIN and CYP3A4 inducers can decrease the plasma concentration of oxycodone [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to oxycodone [see Warnings and Precautions (5.4)].
After stopping a CYP3A4 inducer, as the effects of the inducer decline, the oxycodone plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.
Intervention:

Examples:
If concomitant use is necessary, consider increasing the OXYCONTIN dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider OXYCONTIN dosage reduction and monitor for signs of respiratory depression.
Rifampin, carbamazepine, phenytoin
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Dosage and Administration (2.6), Warnings and Precautions (5.5)].
Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue OXYCONTIN if serotonin syndrome is suspected.
Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)].
Intervention: The use of OXYCONTIN is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples: phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact: May reduce the analgesic effect of OXYCONTIN and/or precipitate withdrawal symptoms.
Intervention: Avoid concomitant use.
Examples: butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact: Oxycodone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of OXYCONTIN and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when OXYCONTIN is used concomitantly with anticholinergic drugs.


Table name:
Beta-Blockers
Clinical Impact:
The concomitant use of beta-blockers and Glucagon for Injection may increase the risk of a temporary increase in heart rate and blood pressure. 
Intervention:
The increase in blood pressure and heart rate may require therapy in patients with coronary artery disease.
Insulin
Clinical Impact:
Insulin reacts antagonistically towards glucagon. 
Intervention:
Monitor blood glucose when Glucagon for Injection is used as a diagnostic aid in diabetes patients.
Indomethacin
Clinical Impact:
The concomitant use of indomethacin and Glucagon for Injection may lead to hypoglycemia.
Intervention:
Monitor blood glucose levels during glucagon treatment of patients taking indomethacin.
Anticholinergic Drugs
Clinical Impact:
The concomitant use of anticholinergic drugs and Glucagon for Injection increase the risk of gastrointestinal adverse reactions due to additive effects on inhibition of gastrointestinal motility.
Intervention:
Concomitant use is not recommended.
Warfarin
Clinical Impact:
Glucagon may increase the anticoagulant effect of warfarin.
Intervention:
Monitor patients for unusual bruising or bleeding, as adjustments in warfarin dosage may be required.


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium ( 2.4 , 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( 7.2)
Antidiabetic agents Carefully monitor blood glucose ( 5.12 , 7.3)


Table name:
Factors
Dosage Adjustments for Aripiprazole
Known CYP2D6 Poor Metabolizers
Administer half of usual dose
Known  CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors
Administer a quarter of usual dose
Strong   CYP2D6 or CYP3A4 inhibitors
Administer half of usual dose
Strong   CYP2D6 and CYP3A4 inhibitors
Administer a quarter of usual dose
Strong  CYP3A4 inducers
Double usual dose over 1 to 2 weeks


Table name:
Bleeding times
Clinical Impact: Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention: This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact: The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention: Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact: Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention: This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.


Table name:
Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Table 18. Summary of Effect of Co-administered Drugs on Exposure to Active Moiety (Risperidone + 9- Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Co-administered Drug  Dosing Schedule  Effect on Active Moeity (Risperidone + 9-Hydroxy-Risperidone (RatioChange relative to reference Risperidone Dose Recommendation 
  Co-administered Drug  Risperidone  AUC  Cmax   
Enzyme (CYP2D6) Inhibitors           
Fluoxetine  20 mg/day  2 or 3 twice daily  1.4  1.5  Re-evaluate dosing. Do not exceed 8 mg/day 
Paroxetine  10 mg/day  4 mg/day  1.3   - Re-evaluate dosing. Do not exceed 8 mg/day
  20 mg/day  4 mg/day  1.6   -   
  40 mg/day  4 mg/day  1.8   -  
Enzyme (CYP3A/PgP inducers) Inducers          
Carbamazepine 573 ± 168 mg/day  3 mg twice daily  0.51 0.55  Titrate dose upwards. Do not exceed twice the patient’s usual dose 
Enzyme (CYP3A) Inhibitors          
Ranitidine  150 mg twice daily  1 mg single dose  1.2  1.4  Dose adjustment not needed 
Cimetidine  400 mg twice daily  1 mg single dose  1.1  1.3  Dose adjustment not needed 
Erythromycin  500 mg four times daily  1 mg single dose  1.1  0.94  Dose adjustment not needed 
Other Drugs           
Amitriptyline  50 mg twice daily  3 mg twice daily  1.2  1.1  Dose adjustment not needed 


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
↓ = Decreased (induces lamotrigine glucuronidation).
↑ = Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.     
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and
150 mcg levonorgestrel
↓ lamotrigine


↓ levonorgestrel
Decreased lamotrigine concentrations approximately 50%.

Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide ↓ lamotrigine



? carbamazepine epoxide
Addition of carbamazepine decreases lamotrigine concentration approximately 40%.

May increase carbamazepine epoxide levels.
Lopinavir/ritonavir ↓ lamotrigine Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir ↓ lamotrigine Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine


? valproate
Increased lamotrigine concentrations slightly more than 2-fold.

There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.


Table name:
Drug/Drug Class
(Mechanism of Interaction by Voriconazole)

Drug Plasma Exposure
(Cmax and AUCτ)

Recommendations for Drug Dosage Adjustment/Comments
Sirolimus*
(CYP3A4 Inhibition)
Significantly Increased
Contraindicated
Rifabutin*
(CYP3A4 Inhibition)
Significantly Increased
Contraindicated
Efavirenz (400 mg q24h)
(CYP450 Induction)
 
Efavirenz (300 mg q24h)
(CYP450 Induction)
Significantly Increased 
 

Slight Increase in AUCτ
Contraindicated
 
 
When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
 
High dose Ritonavir (400 mg q12h)(CYP3A4 Inhibition)
 
Low dose Ritonavir      (100 mg q12h)
 
No Significant Effect of Voriconazole on Ritonavir Cmax or AUCτ
 

Slight Decrease in Ritonavir Cmax and AUCτ
 
Contraindicated because of significant reduction of voriconazole
Cmax and AUCτ
 
 
Coadministration of voriconazole and low dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole Cmax and AUCτ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine
(CYP3A4 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased
Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids
(CYP450 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased
Contraindicated
Cyclosporine*
(CYP3A4 Inhibition)
AUCτ Significantly Increased; No Significant Effect on Cmax
When initiating therapy with voriconazole in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When voriconazole is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
Methadone (CYP3A4 Inhibition)
Increased
Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl (CYP3A4 Inhibition)
Increased
Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary  [see Drug Interactions (7) ]
Alfentanil (CYP3A4 Inhibition)
Significantly Increased
Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with voriconazole. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [see Drug Interactions (7) ].
Oxycodone (CYP3A4 Inhibition)
Significantly Increased
Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7) ].
NSAIDs § including. ibuprofen and diclofenac (CYP2C9 Inhibition)
Increased
Frequent monitoring for adverse events and toxicity related to NSAIDs.

Dose reduction of NSAIDs may be needed [see Drug Interactions (7) ].
Tacrolimus*
(CYP3A4 Inhibition)
Significantly Increased
When initiating therapy with voriconazole in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazole is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin*
(CYP2C9 Inhibition)
Significantly Increased
Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)
Increased
Monitoring for adverse events related to oral contraceptives is recommended during coadministration.
Warfarin*
(CYP2C9 Inhibition)
Prothrombin Time Significantly Increased
Monitor PT or other suitable anti-coagulation tests. Adjustment of
 warfarin dosage may be needed.
Omeprazole*
(CYP2C19/3A4 Inhibition)
Significantly Increased
When initiating therapy with voriconazole  in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors
(CYP3A4 Inhibition)
In Vivo Studies Showed No Significant Effects on Indinavir Exposure
 
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)
No dosage adjustment for indinavir when coadministered with voriconazole
 
Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors
Other NNRTIs
(CYP3A4 Inhibition)
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs
(Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity related to NNRTI
Benzodiazepines
(CYP3A4 Inhibition)
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism
(Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam).
Adjustment of benzodiazepine dosage may be needed.
HMG-CoA Reductase Inhibitors (Statins)
(CYP3A4 Inhibition)
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism
(Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers
(CYP3A4 Inhibition)
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism
(Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics
(CYP2C9 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased
Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids
(CYP3A4 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased
Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed.
Everolimus (CYP3A4 Inhibition)
 
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased
 

Concomitant administration of voriconazole and everolimus is not recommended.


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4 , 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.11 , 7.3)


Table name:
Interacting Drug Interaction
Drugs known to prolong QT interval (e.g., Class IA and Class III anti-arrhythmic agents). Quinine Sulfate Capsules prolong QT interval, ECG abnormalities including QT prolongation and Torsades de Pointes. Avoid concomitant use (5.3).
Other antimalarials (e.g., halofantrine, mefloquine). ECG abnormalities including QT prolongation. Avoid concomitant use (5.3, 7.2).
CYP3A4 inducers or inhibitors Alteration in plasma quinine concentration. Monitor for lack of efficacy or increased adverse events of quinine (7.1).
CYP3A4 and CYP2D6 substrates Quinine is an inhibitor of CYP3A4 and CYP2D6. Monitor for lack of efficacy or increased adverse events of the co-administered drug (7.2).
Digoxin Increased digoxin plasma concentration (5.8, 7.1).


Table name:
NA – Not available/reported
Digoxin concentrations increased greater than 50%
Digoxin Serum Concentration Increase Digoxin AUC Increase Recommendations
Amiodarone 70% NA Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30% to 50% or by modifying the dosing frequency and continue monitoring.
Captopril 58% 39%
Clarithromycin NA 70%
Dronedarone NA 150%
Gentamicin 129% to 212% NA
Erythromycin 100% NA
Itraconazole 80% NA
Lapatinib NA 180%
Nitrendipine 57% 15%
Propafenone NA 60% to 270%
Quinidine 100% NA
Ranolazine 50% NA
Ritonavir NA 86%
Telaprevir 50% 85%
Tetracycline 100% NA
Verapamil 50% to 75% NA
Digoxin concentrations increased less than 50%
Atorvastatin 22% 15% Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15% to 30% or by modifying the dosing frequency and continue monitoring.
Carvedilol 16% 14%
Conivaptan 33% 43%
Diltiazem 20% NA
Indomethacin 40% NA
Nefazodone 27% 15%
Nifedipine 45% NA
Propantheline 24% 24%
Quinine NA 33%
Rabeprazole 29% 19%
Saquinavir 27% 49%
Spironolactone 25% NA
Telmisartan 20% to 49% NA
Ticagrelor 31% 28%
Tolvaptan 30% NA
Trimethoprim 22% to 28% NA
Digoxin concentrations increased, but magnitude is unclear
Alprazolam, azithromycin, cyclosporine, diclofenac, diphenoxylate, epoprostenol, esomeprazole, ibuprofen, ketoconazole, lansoprazole, metformin, omeprazole Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin concentrations decreased
Acarbose, activated charcoal, albuterol, antacids, certain cancer chemotherapy or radiation therapy, cholestyramine, colestipol, extenatide, kaolin-pectin, meals high in bran, metoclopramide, miglitol, neomycin, penicillamine, phenytoin, rifampin, St. John’s Wort, sucralfate and sulfasalazine Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20% to 40% as necessary.


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
 Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration  Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
 Drugs that may alter T 4 and T 3 metabolism
 Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.12, 7.3)


Table name:
Table 2: Clinically Relevant Interactions Affecting Drugs Co-Administered with Rabeprazole Sodium Delayed-Release Tablets
Antiretrovirals
Clinical Impact: The effect of PPI on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir, and nelfinavir) when used concomitantly with rabeprazole may reduce antiviral effect and promote the development of drug resistance. Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with rabeprazole may increase toxicity. There are other antiretroviral drugs which do not result in clinically relevant interactions with rabeprazole.
Intervention: Rilpivirine-containing products: Concomitant use with rabeprazole sodium rabeprazole sodium delayed-release tablets is contraindicated [see Contraindications (4)]. See prescribing information. Atazanavir: See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with rabeprazole sodium delayed-release tablets. See prescribing information for nelfinavir. Saquinavir: See the prescribing information for saquinavir and monitor for potential saquinavir toxicities. Other antiretrovirals: See prescribing information.
Warfarin
Clinical Impact: Increased INR and prothrombin time in patients receiving PPIs, including rabeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death [see Warnings and Precautions (5.2)].
Intervention: Monitor INR and prothrombin time. Dose adjustment of warfarin may be needed to maintain target INR range. See prescribing information for warfarin.
Methotrexate
Clinical Impact: Concomitant use of rabeprazole with methotrexate (primarily at high dose) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of methotrexate with PPIs have been conducted [see Warnings and Precautions (5.9)].
Intervention: A temporary withdrawal of rabeprazole sodium delayed-release tablets may be considered in some patients receiving high dose methotrexate administration.
Digoxin
Clinical Impact: Potential for increased exposure of digoxin [see Clinical Pharmacology (12.3)].
Intervention: Monitor digoxin concentrations. Dose adjustment of digoxin may be needed to maintain therapeutic drug concentrations. See prescribing information for digoxin.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole, itraconazole)
Clinical Impact: Rabeprazole can reduce the absorption of drugs due to its effect on reducing intragastric acidity.
Intervention: Mycophenolate mofetil (MMF): Co-administration of PPIs in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving PPIs and MMF. Use rabeprazole sodium delayed-release tablets with caution in transplant patients receiving MMF. See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact: Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions.
Intervention: See Contraindications and Warnings and Precautions in prescribing information for clarithromycin. See Drug Interactions in prescribing information for amoxicillin.


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
↓= Decreased (induces lamotrigine glucuronidation).
↑= Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine Decreased lamotrigine levels approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? CBZ epoxide May increase CBZ epoxide levels.
Phenobarbital/Primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT) ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine Increased lamotrigine concentrations slightly more than 2-fold.
? valproate Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on
Concentration of Lamotrigine or Concomitant Drug
Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine Decreased lamotrigine concentrations approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? carbamazepine epoxide May increase carbamazepine epoxide levels.
 Lopinavir/ritonavir ↓ lamotrigine Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir ↓ lamotrigine Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine
Increased lamotrigine concentrations slightly more than 2-fold.
? valproate There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.


Table name:
Table 3: Clinically Relevant Interactions Affecting Drugs Co-Administered with Omeprazole and Interaction with Diagnostics
Antiretrovirals
Clinical Impact:
The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology ( 12.3)]. Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see Clinical Pharmacology (12.3)]. There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole.
Intervention:
Rilpivirine-containing products: Concomitant use with omeprazole is contraindicated [see Contraindications ( 4)] .
 
Atazanavir: Avoid concomitant use with omeprazole. See prescribing information for atazanavir for dosing information.
 
Nelfinavir: Avoid concomitant use with omeprazole. See prescribing information for nelfinavir.
 
Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities.
 
Other antiretrovirals: See prescribing information for specific antiretroviral drugs.
Warfarin
Clinical Impact:
Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
Intervention:
Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range.
Methotrexate
Clinical Impact:
Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions ( 5.11)].
Intervention:
A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate.
CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam)
Clopidogrel
Clinical Impact:
Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology ( 12.3)].
There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel .
Intervention:
Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy [see Warnings and Precautions ( 5.6)].
Citalopram
Clinical Impact:
Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology ( 12.3)] .
Intervention:
Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.
Cilostazol
Clinical Impact:
Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology ( 12.3)].
Intervention:
Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.
Phenytoin
Clinical Impact:
Potential for increased exposure of phenytoin.
Intervention:
Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin.
Diazepam
Clinical Impact:
Increased exposure of diazepam [see Clinical Pharmacology ( 12.3)] .
Intervention:
Monitor patients for increased sedation and reduce the dose of diazepam as needed.
Digoxin
Clinical Impact:
Potential for increased exposure of digoxin [see Clinical Pharmacology ( 12.3)].
Intervention:
Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)
Clinical Impact:
Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
Intervention:
Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF [see Clinical Pharmacology ( 12.3)] .
 
See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact:
Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions.
Intervention:
See Contraindications, Warnings and Precautions  in prescribing information for clarithromycin.
 
See  Drug Interactions in prescribing information for amoxicillin.
Tacrolimus
Clinical Impact:
Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19 .
Intervention:
Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact:
Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions ( 5.10), Clinical Pharmacology ( 12.2)] .
Intervention:
Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
Interaction with Secretin Stimulation Test
Clinical Impact:
Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention:
Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology ( 12.2)] .
False Positive Urine Tests for THC
Clinical Impact:
There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.
Intervention:
An alternative confirmatory method should be considered to verify positive results.
Other
Clinical Impact:
There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram).
Intervention:
Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7.1, 7.2, 7.3, 7.4)
Interacting Agents Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone Avoid simvastatin
Gemfibrozil, cyclosporine, danazol Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil Do not exceed 20 mg simvastatin daily
Diltiazem Do not exceed 40 mg simvastatin daily
Grapefruit juice Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor
(boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Drugs That Interfere with Hemostasis
Clinical Impact: • Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone.
• Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of naproxen delayed-release tablets with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity ).
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: Concomitant use of naproxen delayed-release tablets and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity).
Naproxen delayed-release tablets are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).
• In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: • During concomitant use of naproxen delayed-release tablets and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.
• During concomitant use of naproxen delayed-release tablets and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia).
When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention During concomitant use of naproxen delayed-release tablets with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact: The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of naproxen delayed-release tablets and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen delayed-release tablets and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of naproxen delayed-release tablets and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of naproxen delayed-release tablets and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of naproxen delayed-release tablets and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of naproxen delayed-release tablets and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of naproxen delayed-release tablets and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.

NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.

In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact: Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention: Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen delayed-release tablets is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed-release tablets is not recommended.
Cholestyramine
Clinical Impact: Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention: Concomitant administration of cholestyramine with naproxen delayed-release tablets is not recommended.
Probenecid
Clinical Impact: Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention: Patients simultaneously receiving naproxen delayed-release tablets and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact: Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention: Patients simultaneously receiving naproxen delayed-release tablets and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.


Table name:
Summary of antiepileptic drug (AED) interactions with topiramate (7.1).
AED co-administered AED Concentration Topiramate Concentration
Phenytoin NC or 25% increasePlasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. 48% decrease
Carbamazaepine (CBZ) NC 40% decrease
CBZ epoxideIs not administered but is an active metabolite of carbamazepine NC NE
Valproic acid 11% decrease 14% decrease
Phenobarbital NC NE
Primidone NC NE
Lamotrigine NC at TPM doses up to 400mg/day 13% decrease


Table name:
Table 18. Summary of Effect of Co-administered Drugs on Exposure to Active Moiety (Risperidone + 9- Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Co-administered Drug  Dosing Schedule  Effect on Active Moeity (Risperidone + 9-Hydroxy-Risperidone (RatioChange relative to reference Risperidone Dose Recommendation 
  Co-administered Drug  Risperidone  AUC  Cmax   
Enzyme (CYP2D6) Inhibitors           
Fluoxetine  20 mg/day  2 or 3 twice daily  1.4  1.5  Re-evaluate dosing. Do not exceed 8 mg/day 
Paroxetine  10 mg/day  4 mg/day  1.3   - Re-evaluate dosing. Do not exceed 8 mg/day
  20 mg/day  4 mg/day  1.6   -   
  40 mg/day  4 mg/day  1.8   -  
Enzyme (CYP3A/PgP inducers) Inducers          
Carbamazepine 573 ± 168 mg/day  3 mg twice daily  0.51 0.55  Titrate dose upwards. Do not exceed twice the patient’s usual dose 
Enzyme (CYP3A) Inhibitors          
Ranitidine  150 mg twice daily  1 mg single dose  1.2  1.4  Dose adjustment not needed 
Cimetidine  400 mg twice daily  1 mg single dose  1.1  1.3  Dose adjustment not needed 
Erythromycin  500 mg four times daily  1 mg single dose  1.1  0.94  Dose adjustment not needed 
Other Drugs           
Amitriptyline  50 mg twice daily  3 mg twice daily  1.2  1.1  Dose adjustment not needed 


Table name:
Table 2: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 5 mg in BPH patients on stable alpha-blocker therapy (Study 1)
Alpha-Blocker Simultaneous dosing of Vardenafil 5 mg
and Alpha-Blocker,
Placebo-Subtracted
Dosing of Vardenafil 5 mg
and Alpha-Blocker
Separated by 6 Hours,
Placebo-Subtracted
Terazosin
5 or 10 mg daily
Standing SBP -3 (-6.7, 0.1) -4 (-7.4, -0.5)
Supine SBP -4 (-6.7, -0.5) -4 (-7.1, -0.7)
Tamsulosin
0.4 mg daily
Standing SBP
Supine SBP
-6 (-9.9, -2.1)
-4 (-7.0, -0.8)
-4 (-8.3, -0.5)
-5 (-7.9, -1.7)


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C Protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitors (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Bleeding times
Clinical Impact: Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention: This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact: The administration of naproxen may result in increased urinary values for 17 ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention: Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact: Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention: This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.


Table name:
Table 1. Drug Interactions: Pharmacokinetic Parameters for Coadministered Drugs in the Presence of Azithromycin
NA - Not Available * - 90% Confidence interval not reported Mean rifabutin concentrations one-half day after the last dose of rifabutin were 60 ng/mL when coadministered with azithromycin and 71 ng/mL when coadministered with placebo.
Coadministered Drug Dose of Coadministered Drug Dose of Azithromycin n Ratio (with/without azithromycin) of Coadministered Drug Pharmacokinetic Parameters (90% CI); No Effect = 1.00
Mean Cmax Mean AUC
Atorvastatin 10 mg/day x 8 days 500 mg/day PO on days 6 to 8 12 0.83 (0.63 to 1.08) 1.01 (0.81 to 1.25)
Carbamazepine 200 mg/day x 2 days, then 200 mg BID x 18 days 500 mg/day PO for days 16 to 18 7 0.97 (0.88 to 1.06) 0.96 (0.88 to 1.06)
Cetirizine 20 mg/day x 11 days 500 mg PO on day 7, then 250 mg/day on days 8 to 11 14 1.03 (0.93 to 1.14) 1.02 (0.92 to 1.13)
Didanosine 200 mg PO BID x 21 days 1,200 mg/day PO on days 8 to 21 6 1.44 (0.85 to 2.43) 1.14 (0.83 to 1.57)
Efavirenz 400 mg/day x 7 days 600 mg PO on day 7 14 1.04* 0.95*
Fluconazole 200 mg PO single dose 1,200 mg PO single dose 18 1.04 (0.98 to 1.11) 1.01 (0.97 to 1.05)
Indinavir 800 mg TID x 5 days 1,200 mg PO on day 5 18 0.96 (0.86 to 1.08) 0.90 (0.81 to 1.00)
Midazolam 15 mg PO on day 3 500 mg/day PO x 3 days 12 1.27 (0.89 to 1.81) 1.26 (1.01 to 1.56)
Nelfinavir 750 mg TID x 11 days 1,200 mg PO on day 9 14 0.90 (0.81 to 1.01) 0.85 (0.78 to 0.93)
Rifabutin 300 mg/day x 10 days 500 mg PO on day 1, then 250 mg/day on days 2 to 10 6 See footnote below NA
Sildenafil 100 mg on days 1 and 4 500 mg/day PO x 3 days 12 1.16 (0.86 to 1.57) 0.92 (0.75 to 1.12)
Theophylline 4 mg/kg IV on days 1, 11, 25 500 mg PO on day 7, 250 mg/day on days 8 to 11 10 1.19 (1.02 to 1.40) 1.02 (0.86 to 1.22)
Theophylline 300 mg PO BID x 15 days 500 mg PO on day 6, then 250 mg/day on days 7 to 10 8 1.09 (0.92 to 1.29) 1.08 (0.89 to 1.31)
Triazolam 0.125 mg on day 2 500 mg PO on day 1, then 250 mg/day on day 2 12 1.06* 1.02*
Trimethoprim/ Sulfamethoxazole 160 mg/800 mg/day PO x 7 days 1,200 mg PO on day 7 12 0.85 (0.75 to 0.97)/0.90 (0.78 to 1.03) 0.87 (0.80 to 0.95)/0.96 (0.88 to 1.03)
Zidovudine 500 mg/day PO x 21 days 600 mg/day PO x 14 days 5 1.12 (0.42 to 3.02) 0.94 (0.52 to 1.70)
Zidovudine 500 mg/day PO x 21 days 1,200 mg/day PO x 14 days 4 1.31 (0.43 to 3.97) 1.30 (0.69 to 2.43)


Table name:
Table 6: Clinically Significant Drug Interactions with Paricalcitol
CYP3A Inhibitors
Clinical Impact Paricalcitol is partially metabolized by CYP3A. Hence, exposure of paricalcitol will increase upon coadministration with strong CYP3A inhibitors such as but not limited to: boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole.
Intervention Dose adjustment of ZEMPLAR capsules may be necessary. Monitor closely for iPTH and serum calcium concentrations, if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor.
Cholestyramine
Clinical Impact Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of paricalcitol.
Intervention Recommend to take ZEMPLAR capsules at least 1 hour before or 4 to 6 hours after taking cholestyramine (or at as great an interval as possible) to avoid impeding absorption of paricalcitol.
Mineral Oil
Clinical Impact Mineral oil or other substances that may affect absorption of fat may influence the absorption of paricalcitol.
Intervention Recommend to take ZEMPLAR capsules at least 1 hour before or 4 to 6 hours after taking mineral oil (or at as great an interval as possible) to avoid affecting absorption of paricalcitol.


Table name:
Classes of Drugs
5-lipoxygenase Inhibitor Adrenergic Stimulants, Central Alcohol Abuse Reduction Preparations Analgesics Anesthetics, Inhalation Antiandrogen Antiarrhythmics† Antibiotics† Aminoglycosides (oral) Cephalosporins, parenteral Macrolides Miscellaneous Penicillins, intravenous, high dose Quinolones (fluoroquinolones) Sulfonamides, long acting Tetracyclines Anticoagulants Anticonvulsants† Antidepressants† Antimalarial Agents Antineoplastics† Antiparasitic/Antimicrobials























Antiplatelet Drugs/Effects Antithyroid Drugs† Beta-Adrenergic Blockers Cholelitholytic Agents Diabetes Agents, Oral Diuretics† Fungal Medications, Intravaginal, Systemic† Gastric Acidity and Peptic Ulcer Agents† Gastrointestinal Prokinetic Agents Ulcerative Colitis Agents Gout Treatment Agents Hemorrheologic Agents Hepatotoxic Drugs Hyperglycemic Agents Hypertensive Emergency Agents Hypnotics† Hypolipidemics† Bile Acid-Binding Resins† Fibric Acid Derivatives HMG-CoA Reductase Inhibitors†























Leukotriene Receptor Antagonist Monoamine Oxidase Inhibitors Narcotics, prolonged Nonsteroidal Anti- Inflammatory Agents Proton Pump Inhibitors Psychostimulants Pyrazolones Salicylates Selective Serotonin Reuptake Inhibitors Steroids, Adrenocortical† Steroids, Anabolic (17-Alkyl Testosterone Derivatives) Thrombolytics Thyroid Drugs Tuberculosis Agents† Uricosuric Agents Vaccines Vitamins†






















Table name:
Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
  Drugs That are Affected by
Ciprofloxacin
  Drug(s)   Recommendation   Comments
  Tizanidine   Contraindicated   Concomitant administration of tizanidine and
ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)]
  Theophylline   Avoid Use
(Plasma Exposure Likely to be
Increased and Prolonged)
  Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate. [See Warnings and Precautions (5.6).]
  Drugs Known to
 Prolong QT Interval
  Avoid Use   Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.10) and Use in Specific Populations (8.5)].
  Oral antidiabetic drugs   Use with caution
Glucose-lowering effect potentiated
  Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were coadministered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is coadministered with oral antidiabetic drugs. [See Adverse Reactions (6.1).]
  Phenytoin   Use with caution
Altered serum levels of phenytoin (increased and decreased)
  To avoid the loss of seizure control associated with
decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after coadministration of ciprofloxacin with phenytoin.
  Cyclosporine   Use with caution
(transient elevations in serum creatinine)
  Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
  Anti-coagulant drugs   Use with caution
(Increase in anticoagulant effect)
  The risk may vary with the underlying infection, age
and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after coadministration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
  Methotrexate   Use with caution
Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels
  Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
  Ropinirole   Use with caution   Monitoring for ropinirole-related adverse reactions
and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin [see Warnings and Precautions (5.15)].
  Clozapine   Use with caution   Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after coadministration with ciprofloxacin are advised.
  NSAIDs   Use with caution   Non-steroidal anti-inflammatory drugs (but not
acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
  Sildenafil   Use with caution
Two-fold increase in exposure
  Monitor for sildenafil toxicity (see Pharmacokinetics
12.3).
  Duloxetine   Avoid Use
Five-fold increase in duloxetine exposure
  If unavoidable, monitor for duloxetine toxicity
  Caffeine/Xanthine   Use with caution   Ciprofloxacin inhibits the formation of paraxanthine after
  Derivatives   Reduced clearance resulting in elevated levels and prolongation of serum half-life   caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
  Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
  Antacids, Sucralfate,
Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx®
(didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)
  Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation- containing products administration [see Dosage and Administration(2)].   Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
        
  Probenecid   Use with caution
(interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)
  Potentiation of ciprofloxacin toxicity may occur.


Table name:
Antiarrhythmics Dofetilide Concomitant administration with digoxin was associated with a higher rate of torsades de pointes.
Sotalol Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
Parathyroid Hormone Analog Teriparatide Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid Supplement Thyroid Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics Epinepherine Can increase the risk of cardiac arrhythmias.
Norepinephrine
Dopamine
Neuromuscular Blocking Agents Succinylcholine May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.
Supplements Calcium If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic Blockers and Calcium Channel Blockers Additive effects on AV node conduction can result in complete heart block.
Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel Blocker Ivabradine can increase the risk of bradycardia.


Table name:
Specific Drugs Reported
also: diet high in vitamin K
unreliable PT/INR determinations
†Increased and decreased PT/INR responses have been reported.
alcohol†
aminoglutethimide
amobarbital
atorvastatin†
azathioprine
butabarbital
butalbital
carbamazepine
chloral hydrate†
chlordiazepoxide
chlorthalidone
cholestyramine†
clozapine
corticotropin
cortisone
cyclophosphamide†
dicloxacillin
ethchlorvynol
glutethimide
griseofulvin
haloperidol
meprobamate
6-mercaptopurine
methimazole†
moricizine hydrochloride†
nafcillin
paraldehyde
pentobarbital
phenobarbital
phenytoin†
pravastatin†
prednisone†
primidone
propylthiouracil†
raloxifene
ranitidine†
rifampin
secobarbital
spironolactone
sucralfate
trazodone
vitamin C (high dose)
vitamin K
warfarin underdosage


Table name:
Interacting Agent Examples
Drugs that may increase phenytoin serum levels
Antiepileptic drugs Ethosuximide, felbamate, oxcarbazepine, methsuximide, topiramate
Azoles Fluconazole, ketoconazole, itraconazole, miconazole, voriconazole
Antineoplastic agents Capecitabine, fluorouracil
Antidepressants Fluoxetine, fluvoxamine, sertraline
Gastric acid reducing agents H2 antagonists (cimetidine), omeprazole
Sulfonamides Sulfamethizole, sulfaphenazole, sulfadiazine, sulfamethoxazole-trimethoprim
Other Acute alcohol intake, amiodarone, chloramphenicol, chlordiazepoxide, disulfiram, estrogen, fluvastatin, isoniazid, methylphenidate, phenothiazines, salicylates, ticlopidine, tolbutamide, trazodone, warfarin
Drugs that may decrease phenytoin serum levels
Antacidsa Calcium carbonate, aluminum hydroxide, magnesium hydroxide Prevention or Management: Phenytoin and antacids should not be taken at the same time of day
Antineoplastic agents usually in combination Bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate
Antiviral agents Fosamprenavir, nelfinavir, ritonavir
Antiepileptic drugs Carbamazepine, vigabatrin
Other Chronic alcohol abuse, diazepam, diazoxide, folic acid, reserpine, rifampin, St. John’s wortb, sucralfate, theophylline
Drugs that may either increase or decrease phenytoin serum levels
Antiepileptic drugs Phenobarbital, valproate sodium, valproic acid


Table name:
Table 2. Steady-State Plasma Concentrations of Felbamate when Coadministered with Other AEDs
AED Coadministered AED Concentration Felbamate Concentration
Phenytoin
Valproate No significant effect.
Carbamazepine (CBZ)
Not administered but an active metabolite of carbamazepine.CBZ epoxide

 
Phenobarbital


Table name:
Table 2: Clinically Significant Drug Interactions with Opana
Alcohol
Clinical Impact: The concomitant use of alcohol with OPANA can result in an increase of oxymorphone plasma levels and potentially fatal overdose of oxymorphone.
Intervention: Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products containing alcohol while on OPANA therapy [see Clinical Pharmacology (12.3)].
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines and other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.4)].
Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue OPANA if serotonin syndrome is suspected.
Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)]. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
Intervention: The use of OPANA is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples: phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact: May reduce the analgesic effect of OPANA and/or precipitate withdrawal symptoms.
Intervention: Avoid concomitant use.
Examples: butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact: Oxymorphone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of OPANA and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when OPANA is used concomitantly with anticholinergic drugs.
Anticholinergic Drugs
Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when OPANA is used concomitantly with anticholinergic drugs.
Cimetidine
Clinical Impact: Cimetidine can potentiate opioid-induced respiratory depression.
Intervention: Monitor patients for respiratory depression when OPANA and cimetidine are used concurrently.


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may
result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-
   containing radiographic
   contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which
may result in hyperthyroidism
Amiodarone
Iodide (including iodine-
containing Radiographic
contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase Drugs that may decrease
serum TBG concentration serum TBG concentration
Clofibrate Androgens / Anabolic Steroids
Estrogen-containing oral Asparaginase
   contraceptives Glucocorticoids
Estrogens (oral) Slow-Release Nicotinic Acid
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal
Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake
Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
NITROPRUSSIDE
Para-aminosalicylate sodium
Perphenazine
Resorcinol
 (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
AED Coadministered AED Concentration Topiramate Concentration
Phenytoin NC or 25% increasea 48% decrease
Carbamazepine (CBZ) NC 40% decrease
CBZ epoxideb NC NE
Valproic acid 11% decrease 14% decrease
Phenobarbital NC NE
Primidone NC NE
Lamotrigine NC at TPM doses up to 400 mg/day 13% decrease


Table name:
Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug Dosing Schedule Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio Change relative to reference) Risperidone Dose Recommendation
Coadministered Drug Risperidone AUC Cmax
Enzyme (CYP2D6) Inhibitors
Fluoxetine 20 mg/day 2 or 3 mg twice daily 1.4 1.5 Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine 10 mg/day 4 mg/day 1.3 - Re-evaluate dosing. Do not exceed 8 mg/day
20 mg/day 4 mg/day 1.6 -
40 mg/day 4 mg/day 1.8 -
Enzyme (CYP3A/PgP inducers) Inducers
Carbamazepine 573 ± 168 mg/day 3 mg twice daily 0.51 0.55 Titrate dose upwards. Do not exceed twice the patient's usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine 150 mg twice daily 1 mg single dose 1.2 1.4 Dose adjustment not needed
Cimetidine 400 mg twice daily 1 mg single dose 1.1 1.3 Dose adjustment not needed
Erythromycin 500 mg four times daily 1 mg single dose 1.1 0.94 Dose adjustment not needed
Other Drugs
Amitriptyline 50 mg twice daily 3 mg twice daily 1.2 1.1 Dose adjustment not needed


Table name:
Factors Dosage Adjustment of ABILIFY
Known CYP2D6 Poor Metabolizers Administer half of usual dose
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors Administer half of usual dose
Strong CYP2D6 and CYP3A4 inhibitors Administer a quarter of usual dose
Strong CYP3A4 inducers Double usual dose over 1 to 2 weeks


Table name:
DRUG INTERACTIONS
CNS depressants: Enhanced CNS-depressant effects with combination use. Use with alcohol causes additive psychomotor impairment (7.1) Imipramine: Decreased alertness observed with combination use. (7.1) Chlorpromazine:Impaired alertness and psychomotor performance observed with combination use (7.1) Rifampin: Combination use decreases exposure to and effects of zolpidem (7.2) Ketoconazole: Combination use increases exposure to and effect of zolpidem (7.2)


Table name:
Factors
Dosage Adjustment for Aripiprazole tablets
Known CYP2D6 Poor Metabolizers
Administer half of usual dose
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors
Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors
Administer half of usual dose
Strong CYP2D6 and CYP3A4 inhibitors
Administer a quarter of usual dose
Strong CYP3A4 inducers
Double usual dose over 1 to 2 weeks


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T 4 and T 3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
  Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration   Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT 4. Continued administration results in a decrease in serum T 4 and normal FT 4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T 4 and T 3 to TBG and transthyretin. An initial increase in serum FT 4, is followed by return of FT 4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T 4 levels may decrease by as much as 30%.
  Drugs that may alter T 4 and T 3 metabolism
  Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T 4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T 4 to T 3, leading to decreased T 3 levels. However, serum T 4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T 3 and T 4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T 3 concentrations by 30% with minimal change in serum T 4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T 3 and T 4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
  Bleeding times
  Clinical Impact:  Naproxen may decrease platelet aggregation and prolong bleeding time.
  Intervention:  This effect should be kept in mind when bleeding times are determined.
  Porter-Silber test
  Clinical Impact:  The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
  Intervention:  Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
  Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
  Clinical Impact:  Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
  Intervention:  This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may
result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-
   containing radiographic
   contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which
may result in hyperthyroidism
Amiodarone
Iodide (including iodine-
containing Radiographic
contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase Drugs that may decrease
serum TBG concentration serum TBG concentration
Clofibrate Androgens / Anabolic Steroids
Estrogen-containing oral Asparaginase
   contraceptives Glucocorticoids
Estrogens (oral) Slow-Release Nicotinic Acid
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal
Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake
Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
NITROPRUSSIDE
Para-aminosalicylate sodium
Perphenazine
Resorcinol
 (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Table 6. Drugs That Should Not Be Coadministered With RESCRIPTOR
Drug Class: Drug Name Clinical Comment
Anticonvulsant agents: Phenytoin, phenobarbital, carbamazepine May lead to loss of virologic response and possible resistance to RESCRIPTOR or to the class of NNRTIs.
Antihistamines: Astemizole, terfenadine CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Antimycobacterials: Rifabutin,a rifampin a May lead to loss of virologic response and possible resistance to RESCRIPTOR or to the class of NNRTIs or other coadministered antiviral agents.
Ergot Derivatives: Dihydroergotamine, ergonovine, ergotamine, methylergonovine CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
GI motility agent: Cisapride CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Herbal Products: St. John’s wort
( hypericum perforatum)
May lead to loss of virologic response and possible resistance to RESCRIPTOR or to the class of NNRTIs.
HMG-CoA reductase inhibitors: Lovastatin, simvastatin Potential for serious reactions such as risk of myopathy including rhabdomyolysis.
Neuroleptic: Pimozide CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Sedative/hypnotics: Alprazolam, midazolam, triazolam CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression.


Table name:
Summary of AED interactions with topiramate (7.1).
AED Co-administered AED Concentration Topiramate Concentration
Phenytoin NC or 25% increasea 48% decrease
Carbamazepine (CBZ) NC 40% decrease
CBZ epoxideb NC NE
Valproic acid 11% decrease 14% decrease
Phenobarbital NC NE
Primidone NC NE
Lamotrigine NC at TPM doses up to 400mg/day 13% decrease


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
  Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)   Avoid atorvastatin
  HIV protease inhibitor (lopinavir plus ritonavir)   Use with caution and lowest dose necessary
  Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)   Do not exceed 20 mg atorvastatin daily
  HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
  Do not exceed 40 mg atorvastatin daily


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Table 3: Clinically Significant Drug Interactions with Celecoxib
Drugs  That  Interfere  with  Hemostasis
Clinical  Impact :
•  Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of celecoxib and anticoagulants have an increased risk of serious bleeding compared to the 
use of either drug alone. 

•  Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an
NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention :
•  Monitor patients with concomitant use of celecoxib with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine  reuptake inhibitors (SNRIs) for signs of bleeding [see WARNINGS AND PRECAUTIONS (5.11)].
Aspirin
Clinical  Impact :
•  Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study,  the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see WARNINGS AND  PRECAUTIONS (5.2)]. In two studies in healthy volunteers, and in patients with osteoarthritis and established heart disease respectively, celecoxib capsules (200 to 400 mg daily) has demonstrated a lack of interference with the cardioprotective antiplatelet effect of aspirin (100 to 325 mg).
Intervention :
Concomitant use of celecoxib and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see WARNINGS AND PRECAUTIONS (5.11)]. Celecoxib capsules are not a substitute for low dose aspirin for cardiovascular protection.
ACE  Inhibitors Angiotensin  Receptor  Blockers and  Beta - Blockers
Clinical  Impact :
•  NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). 
•  In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration 
of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention :
•  During concomitant use of celecoxib and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.  •  During concomitant use of celecoxib and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see WARNINGS AND PRECAUTIONS (5.6)]. • When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical  Impact :
Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. 
This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention :
During concomitant use of celecoxib with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects  [see WARNINGS AND PRECAUTIONS (5.6)].
Digoxin
Clinical  Impact :
The concomitant use of celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention :
During concomitant use of celecoxib and digoxin, monitor serum digoxin levels.
Lithium
Clinical  Impact :
NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by 
approximately 20%.
This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention :
During concomitant use of celecoxib and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical  Impact :
Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). 

Celecoxib capsules has no effect on methotrexate pharmacokinetics.
Intervention :
During concomitant use of celecoxib and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical  Impact :
Concomitant use of celecoxib and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention :
During concomitant use of celecoxib and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs  and  Salicylates
Clinical  Impact :
Concomitant use of celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy  [see WARNINGS AND PRECAUTIONS (5.2)].
Intervention :
The concomitant use of celecoxib with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical  Impact :
Concomitant use of celecoxib and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention :
During concomitant use of celecoxib and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. 
NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. 
In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing 
for at least five days before, the day of, and two days following pemetrexed administration.
CYP2C9  Inhibitors  or  inducers
Clinical  Impact :
Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Co-administration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may 
enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of celecoxib.
Intervention
Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers.  [see CLINICAL PHARMACOLOGY (12.3)].
CYP2D6  substrates
Clinical  Impact :
In  vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is a potential for an in  vivo drug interaction with drugs that are metabolized by CYP2D6 
(e.g. atomoxetine), and celecoxib may enhance the exposure and toxicity of these drugs.
Intervention
Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2D6 substrates.  [see CLINICAL PHARMACOLOGY (12.3)].
Corticosteroids 
Clinical  Impact :
Concomitant use of corticosteroids with celecoxib capsules may increase the risk of GI ulceration or bleeding.
Intervention
Monitor patients with concomitant use of celecoxib capsules with corticosteroids for signs of bleeding [see WARNINGS AND PRECAUTIONS (5.2)].


Table name:
Table 8: Clinically Significant Drug Interactions with Clarithromycin
Drugs That Are Affected By Clarithromycin
Drug(s) with Pharmacokinetics Affected by Clarithromycin Recommendation Comments
Antiarrhythmics: Disopyramide Quinidine Dofetilide Amiodarone Sotalol Procainamide Digoxin Not Recommended Use With Caution Disopyramide, Quinidine: There have been postmarketing reports of torsades de pointes occurring with concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QTc prolongation during coadministration of clarithromycin with these drugs [see Warnings and Precautions (5.3)]. Serum concentrations of these medications should also be monitored. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with disopyramide and quinidine. There have been postmarketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide. Therefore, blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide. Digoxin: Digoxin is a substrate for P-glycoprotein (Pgp) and clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are coadministered, inhibition of Pgp by clarithromycin may lead to increased exposure of digoxin. Elevated digoxin serum concentrations in patients receiving clarithromycin and digoxin concomitantly have been reported in postmarketing surveillance. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Monitoring of serum digoxin concentrations should be considered, especially for patients with digoxin concentrations in the upper therapeutic range.
Oral Anticoagulants: Warfarin Use With Caution Oral anticoagulants: Spontaneous reports in the postmarketing period suggest that concomitant administration of clarithromycin and oral anticoagulants may potentiate the effects of the oral anticoagulants. Prothrombin times should be carefully monitored while patients are receiving clarithromycin and oral anticoagulants simultaneously [see Warnings and Precautions (5.4)].
Antiepileptics: Carbamazepine Use With Caution Carbamazepine: Concomitant administration of single doses of clarithromycin and carbamazepine has been shown to result in increased plasma concentrations of carbamazepine. Blood level monitoring of carbamazepine may be considered. Increased serum concentrations of carbamazepine were observed in clinical trials with clarithromycin. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with carbamazepine.
Antifungals: Itraconazole Fluconazole Use With Caution No Dose Adjustment Itraconazole: Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when administered concomitantly (see also Itraconazole under “Drugs That Affect Clarithromycin” in the table below). Clarithromycin may increase the plasma concentrations of itraconazole. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions. Fluconazole: [see Pharmacokinetics (12.3)]
Anti-Gout Agents: Colchicine (in patients with renal or hepatic impairment) Colchicine (in patients with normal renal and hepatic function) Contraindicated Use With Caution Colchicine: Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. The dose of colchicine should be reduced when coadministered with clarithromycin in patients with normal renal and hepatic function [see Contraindications (4.4) and Warnings and Precautions (5.4)].
Antipsychotics: Pimozide Quetiapine Contraindicated Pimozide: [see Contraindications (4.2)] Quetiapine: Quetiapine is a substrate for CYP3A4, which is inhibited by clarithromycin. Coadministration with clarithromycin could result in increased quetiapine exposure and possible quetiapine related toxicities. There have been postmarketing reports of somnolence, orthostatic hypotension, altered state of consciousness, neuroleptic malignant syndrome, and QT prolongation during concomitant administration. Refer to quetiapine prescribing information for recommendations on dose reduction if coadministered with CYP3A4 inhibitors such as clarithromycin.
Antispasmodics: Tolterodine (patients deficient in CYP2D6 activity) Use With Caution Tolterodine: The primary route of metabolism for tolterodine is via CYP2D6. However, in a subset of the population devoid of CYP2D6, the identified pathway of metabolism is via CYP3A. In this population subset, inhibition of CYP3A results in significantly higher serum concentrations of tolterodine. Tolterodine 1 mg twice daily is recommended in patients deficient in CYP2D6 activity (poor metabolizers) when coadministered with clarithromycin.
Antivirals: Atazanavir Saquinavir (in patients with decreased renal function) Ritonavir Etravirine Maraviroc Boceprevir (in patients with normal renal function) Didanosine Zidovudine Use With Caution No Dose Adjustment Atazanavir: Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction (see Atazanavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)]. Saquinavir: Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A and there is evidence of a bi-directional drug interaction (see Saquinavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)]. Ritonavir, Etravirine: (see Ritonavir and Etravirine under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)]. Maraviroc: Clarithromycin may result in increases in maraviroc exposures by inhibition of CYP3A metabolism. See Selzentry® prescribing information for dose recommendation when given with strong CYP3A inhibitors such as clarithromycin. Boceprevir: Both clarithromycin and boceprevir are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when coadministered. No dose adjustments are necessary for patients with normal renal function (see Victrelis® prescribing information). Zidovudine: Simultaneous oral administration of clarithromycin immediate-release tablets and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine concentrations. Administration of clarithromycin and zidovudine should be separated by at least two hours [see Pharmacokinetics (12.3)].

The impact of coadministration of clarithromycin extended-release tablets or granules and zidovudine has not been evaluated.
Calcium Channel Blockers: Verapamil Amlodipine Diltiazem Nifedipine Use With Caution Verapamil: Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent verapamil, [see Warnings and Precautions (5.4)]. Amlodipine, Diltiazem: [see Warnings and Precautions (5.4)] Nifedipine: Nifedipine is a substrate for CYP3A. Clarithromycin and other macrolides are known to inhibit CYP3A. There is potential of CYP3A-mediated interaction between nifedipine and clarithromycin. Hypotension and peripheral edema were observed when clarithromycin was taken concomitantly with nifedipine [see Warnings and Precautions (5.4)].
Ergot Alkaloids: Ergotamine Dihydroergotamine Contraindicated Ergotamine, Dihydroergotamine: Postmarketing reports indicate that coadministration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system [see Contraindications (4.6)].
Gastroprokinetic Agents: Cisapride Contraindicated Cisapride: [see Contraindications (4.2)]
HMG-CoA Reductase Inhibitors: Lovastatin Simvastatin Atorvastatin Pravastatin Fluvastatin Contraindicated Use With Caution No Dose Adjustment Lovastatin, Simvastatin, Atorvastatin, Pravastatin, Fluvastatin: [see Contraindications (4.5) and Warnings and Precautions (5.4)]
Hypoglycemic Agents: Nateglinide Pioglitazone Repaglinide Rosiglitazone Insulin Use With Caution Nateglinide, Pioglitazone, Repaglinide, Rosiglitazone: [see Warnings and Precautions (5.4) and Adverse Reactions (6.2)] Insulin: [see Warnings and Precautions (5.4) and Adverse Reactions (6.2)]
Immunosuppressants: Cyclosporine Tacrolimus Use With Caution Cyclosporine: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with cyclosporine. Tacrolimus: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with tacrolimus.
Phosphodiesterase inhibitors: Sildenafil Tadalafil Vardenafil Use With Caution Sildenafil, Tadalafil, Vardenafil: Each of these phosphodiesterase inhibitors is primarily metabolized by CYP3A, and CYP3A will be inhibited by concomitant administration of clarithromycin. Coadministration of clarithromycin with sildenafil, tadalafil, or vardenafil will result in increased exposure of these phosphodiesterase inhibitors. Coadministration of these phosphodiesterase inhibitors with clarithromycin is not recommended. Increased systemic exposure of these drugs may occur with clarithromycin; reduction of dosage for phosphodiesterase inhibitors should be considered (see their respective prescribing information).
Proton Pump Inhibitors: Omeprazole No Dose Adjustment Omeprazole: The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when coadministered with clarithromycin as a result of increased omeprazole exposures [see Pharmacokinetics (12.3)] (see also Omeprazole under “Drugs That Affect Clarithromycin” in the table below).
Xanthine Derivatives: Theophylline Use With Caution Theophylline: Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serum theophylline concentrations [see Pharmacokinetics (12.3)]. Monitoring of serum theophylline concentrations should be considered for patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range.
Triazolobenzodiazepines and Other Related Benzodiazepines: Midazolam Alprazolam Triazolam Temazepam Nitrazepam Lorazepam Use With Caution No Dose Adjustment Midazolam: When oral midazolam is coadministered with clarithromycin, dose adjustments may be necessary and possible prolongation and intensity of effect should be anticipated [see Warnings and Precautions (5.4) and Pharmacokinetics (12.3)]. Triazolam, Alprazolam: Caution and appropriate dose adjustments should be considered when triazolam or alprazolam is coadministered with clarithromycin. There have been postmarketing reports of drug interactions and central nervous system (CNS) effects (e.g., somnolence and confusion) with the concomitant use of clarithromycin and triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested. In postmarketing experience, erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines. Temazepam, Nitrazepam, Lorazepam: For benzodiazepines which are not metabolized by CYP3A (e.g., temazepam, nitrazepam, lorazepam), a clinically important interaction with clarithromycin is unlikely.
Cytochrome P450 Inducers: Rifabutin Use With Caution Rifabutin: Concomitant administration of rifabutin and clarithromycin resulted in an increase in rifabutin, and decrease in clarithromycin serum levels together with an increased risk of uveitis (see Rifabutin under “Drugs That Affect Clarithromycin” in the table below).
Other Drugs Metabolized by CYP3A: Alfentanil Bromocriptine Cilostazol Methylprednisole Vinblastine Phenobarbital St. John’s Wort Use With Caution There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with alfentanil, methylprednisolone, cilostazol, bromocriptine, vinblastine, phenobarbital, and St. John’s Wort.
Other Drugs Metabolized by CYP450 Isoforms Other than CYP3A: Hexobarbital Phenytoin Valproate Use With Caution There have been postmarketing reports of interactions of clarithromycin with drugs not thought to be metabolized by CYP3A, including hexobarbital, phenytoin, and valproate.
Drugs that Affect Clarithromycin
Drug(s) that Affect the Pharmacokinetics of Clarithromycin Recommendation Comments
Antifungals: Itraconazole Use With Caution Itraconazole: Itraconazole may increase the plasma concentrations of clarithromycin. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions (see also Itraconazole under “Drugs That Are Affected By Clarithromycin” in the table above).
Antivirals: Atazanavir Ritonavir (in patients with decreased renal function) Saquinavir (in patients with decreased renal function) Etravirine Saquinavir (in patients with normal renal function) Ritonavir (in patients with normal renal function) Use With Caution No Dose Adjustments Atazanavir: When clarithromycin is coadministered with atazanavir, the dose of clarithromycin should be decreased by 50% [see Clinical Pharmacology (12.3)]. Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is coadministered with atazanavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium complex. Doses of clarithromycin greater than 1000 mg per day should not be coadministered with protease inhibitors. Ritonavir: Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is coadministered with ritonavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium [see Pharmacokinetics (12.3)]. Doses of clarithromycin greater than 1000 mg per day should not be coadministered with protease inhibitors. Saquinavir: When saquinavir is coadministered with ritonavir, consideration should be given to the potential effects of ritonavir on clarithromycin (refer to ritonavir above) [see Pharmacokinetics (12.3)]. Etravirine: Clarithromycin exposure was decreased by etravirine; however, concentrations of the active metabolite, 14-OH-clarithromycin, were increased. Because 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered; therefore alternatives to clarithromycin should be considered for the treatment of MAC.
Proton Pump Inhibitors: Omeprazole Use With Caution Omeprazole: Clarithromycin concentrations in the gastric tissue and mucus were also increased by concomitant administration of omeprazole [see Pharmacokinetics (12.3)].
Miscellaneous Cytochrome P450 Inducers: Efavirenz Nevirapine Rifampicin Rifabutin Rifapentine Use With Caution Inducers of CYP3A enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine will increase the metabolism of clarithromycin, thus decreasing plasma concentrations of clarithromycin, while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. Alternative antibacterial treatment should be considered when treating patients receiving inducers of CYP3A. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with rifabutin (see Rifabutin under “Drugs That Are Affected By Clarithromycin” in the table above).


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
 Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration  Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
 Drugs that may alter T 4 and T 3 metabolism
 Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( 7.2)
Antidiabetic agents Carefully monitor blood glucose ( 5.12, 7.3)


Table name:
Interacting DrugInteracting Drug InteractionInteraction
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products.
Warfarin
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( 7.2)
Antidiabetic agents
Carefully monitor blood glucose ( 5.11, 7.3)


Table name:
Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.*
albuterol,  systemic and inhaledfelodipinefinasteridenizatidinenorfloxacin
amoxicillinhydrocortisoneofloxacin
ampicillin,   with or without sulbactamisofluraneisoniazidomeprazoleprednisone, prednisolone
atenololisradipineranitidine
azithromycininfluenza vaccinerifabutin
caffeine,   dietary ingestionketoconazolelomefloxacinroxithromycinsorbitol
cefaclormebendazole        (purgative doses do not
co-trimoxazole  (trimethoprim and sulfamethoxazole)medroxyprogesteronemethylprednisolone   inhibit theophylline   absorption)
diltiazemmetronidazolesucralfate
dirithromycinmetoprololterbutaline, systemic
enfluranenadololterfenadine
famotidinenifedipinetetracycline
tocainide
*Refer to PRECAUTIONS, Drug Interactions for information regarding table.


Table name:
Table 2: Drug Interactions: Pharmacokinetic Parameters for Indinavir in the Presence of the Coadministered Drug (See PRECAUTIONS, Table 9 for Recommended Alterations in Dose or Regimen)
Coadministered drug Dose of Coadministered drug (mg) Dose of CRIXIVAN
(mg)
n Ratio (with/without coadministered drug) of Indinavir
Pharmacokinetic Parameters
(90% CI); No Effect = 1.00
Cmax AUC Cmin
All interaction studies conducted in healthy, HIV-negative adult subjects, unless otherwise indicated.
Cimetidine 600 twice daily,
6 days
400 single dose 12 1.07
(0.77, 1.49)
0.98
(0.81, 1.19)
0.82
(0.69, 0.99)
Clarithromycin 500 q12h,
7 days
800 three times
daily, 7 days
10 1.08
(0.85, 1.38)
1.19
(1.00, 1.42)
1.57
(1.16, 2.12)
Delavirdine 400 three times daily 400 three times
daily, 7 days
28 0.64Relative to indinavir 800 mg three times daily alone.
(0.48, 0.86)
No significant change 2.18
(1.16, 4.12)
Delavirdine 400 three times daily 600 three times
daily, 7 days
28 No significant change 1.53
(1.07, 2.20)
3.98
(2.04, 7.78)
EfavirenzStudy conducted in HIV-positive subjects. 600 once daily,
10 days
1000 three times
daily, 10 days
20
After morning dose No significant change 0.67
(0.61, 0.74)
0.61
(0.49, 0.76)
After afternoon dose No significant change 0.63
(0.54, 0.74)
0.48
(0.43, 0.53)
After evening dose 0.71
(0.57, 0.89)
0.54
(0.46, 0.63)
0.43
(0.37, 0.50)
Fluconazole 400 once daily,
8 days
1000 three times daily, 7 days 11 0.87
(0.72, 1.05)
0.76
(0.59, 0.98)
0.90
(0.72, 1.12)
Grapefruit Juice 8 oz. 400 single dose 10 0.65
(0.53, 0.79)
0.73
(0.60, 0.87)
0.90
(0.71, 1.15)
Isoniazid 300 once daily in the morning,
8 days
800 three times daily, 7 days 11 0.95
(0.88, 1.03)
0.99
(0.87, 1.13)
0.89
(0.75, 1.06)
Itraconazole 200 twice daily,
7 days
600 three times
daily, 7 days
12 0.78
(0.69, 0.88)
0.99
(0.91, 1.06)
1.49
(1.28, 1.74)
Ketoconazole 400 once daily,
7 days
600 three times
daily, 7 days
12 0.69
(0.61, 0.78)
0.80
(0.74, 0.87)
1.29
(1.11, 1.51)
400 once daily,
7 days
400 three times
daily, 7 days
12 0.42
(0.37, 0.47)
0.44
(0.41, 0.48)
0.73
(0.62, 0.85)
Methadone 20-60 once daily in the morning,
8 days
800 three times
daily, 8 days
10 See text below for discussion of interaction.
Quinidine 200 single dose 400 single dose 10 0.96
(0.79, 1.18)
1.07
(0.89, 1.28)
0.93
(0.73, 1.19)
Rifabutin 150 once daily in the morning,
10 days
800 three times
daily, 10 days
14 0.80
(0.72, 0.89)
0.68
(0.60, 0.76)
0.60
(0.51, 0.72)
Rifabutin 300 once daily in the morning,
10 days
800 three times
daily, 10 days
10 0.75
(0.61, 0.91)
0.66
(0.56, 0.77)
0.61
(0.50, 0.75)
Rifampin 600 once daily in the morning,
8 days
800 three times
daily, 7 days
12 0.13
(0.08, 0.22)
0.08
(0.06, 0.11)
Not Done
Ritonavir 100 twice daily,
14 days
800 twice
daily, 14 days
10, 16Comparison to historical data on 16 subjects receiving indinavir alone. See text below for discussion of interaction.
Ritonavir 200 twice daily,
14 days
800 twice
daily,14 days
9, 16 See text below for discussion of interaction.
Sildenafil 25 single dose 800 three times daily 6 See text below for discussion of interaction.
St. John's wort
(Hypericum perforatum,
standardized to 0.3 % hypericin)
300 three times daily with meals,
14 days
800 three times daily 8 Not Available 0.46
(0.34, 0.58)95% CI.
0.19
(0.06, 0.33)
Stavudine (d4T) 40 twice daily,
7 days
800 three times
daily, 7 days
11 0.95
(0.80, 1.11)
0.95
(0.80, 1.12)
1.13
(0.83, 1.53)
Trimethoprim/
Sulfamethoxazole
800 Trimethoprim/
160 Sulfamethoxazole q12h, 7 days
400 four times
daily, 7 days
12 1.12
(0.87, 1.46)
0.98
(0.81, 1.18)
0.83
(0.72, 0.95)
Zidovudine 200 three times daily, 7 days 1000 three times
daily, 7 days
12 1.06
(0.91, 1.25)
1.05
(0.86, 1.28)
1.02
(0.77, 1.35)
Zidovudine/
Lamivudine
(3TC)
200/150 three times daily, 7 days 800 three times
daily, 7 days
6, 9Parallel group design; n for indinavir + coadministered drug, n for indinavir alone. 1.05
(0.83, 1.33)
1.04
(0.67, 1.61)
0.98
(0.56, 1.73)


Table name:
Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug Dosing Schedule Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (RatioChange relative to reference) Risperidone Dose Recommendation
Coadministered Drug Risperidone AUC Cmax
Enzyme (CYP2D6) Inhibitors
Fluoxetine 20 mg/day 2 or 3 mg twice daily 1.4 1.5 Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine 10 mg/day 4 mg/day 1.3 - Re-evaluate dosing. Do not exceed 8 mg/day
20 mg/day 4 mg/day 1.6 -
40 mg/day 4 mg/day 1.8 -
Enzyme (CYP3A/PgP inducers) Inducers
Carbamazepine 573 ± 168 mg/day 3 mg twice daily 0.51 0.55 Titrate dose upwards. Do not exceed twice the patient's usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine 150 mg twice daily 1 mg single dose 1.2 1.4 Dose adjustment not needed
Cimetidine 400 mg twice daily 1 mg single dose 1.1 1.3 Dose adjustment not needed
Erythromycin 500 mg four times daily 1 mg single dose 1.1 0.94 Dose adjustment not needed
Other Drugs
Amitriptyline 50 mg twice daily 3 mg twice daily 1.2 1.1 Dose adjustment not needed


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents
Prescribing Recommendations
Strong CYP34A inhibitors (e.g. itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol
Contraindicated with simvastatin
Verapamil, diltiazem
Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine
Do not exceed 20 mg simvastatin daily
Grapefruit juice
Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme
Inhibitors
Inducers
CYP2C9 
amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast
aprepitant, bosentan, carbamazepine, phenobarbital, rifampin 
CYP1A2 
acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton
montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking 
CYP3A4 
alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton
armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide 


Table name:
Table 5. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class:
Drug Name
Effect on Concentration of Ritonavir or Concomitant Drug Clinical Comment
  HIV-Antiviral Agents  
HIV-1 Protease Inhibitor:
atazanavir
darunavir
fosamprenavir
↑ amprenavir
↑ atazanavir
↑ darunavir
See the complete prescribing information for fosamprenavir, atazanavir, darunavir for details on co-administration with ritonavir.
HIV-1 Protease Inhibitor:
indinavir
↑ indinavir Appropriate doses for this combination, with respect to efficacy and safety, have not been established.
HIV-1 Protease Inhibitor:
saquinavir
↑ saquinavir See the complete prescribing information for saquinavir for details on co-administration of saquinavir and ritonavir.
Saquinavir/ritonavir in combination with rifampin is not recommended due to the risk of severe hepatotoxicity (presenting as increased hepatic transaminases) if the three drugs are given together.
HIV-1 Protease Inhibitor:
tipranavir
↑ tipranavir See the complete prescribing information for tipranavir for details on co-administration of tipranavir and ritonavir.
Non-Nucleoside Reverse Transcriptase Inhibitor:
delavirdine
↑ ritonavir Appropriate doses of this combination with respect to safety and efficacy have not been established.
HIV-1 CCR5 – antagonist: maraviroc ↑ maraviroc See the complete prescribing information for maraviroc for details on co-administration of maraviroc and ritonavir-containing protease inhibitors.
Integrase Inhibitor:
raltegravir
↓ raltegravir The effects of ritonavir on raltegravir with ritonavir dosage regimens greater than 100 mg twice daily have not been evaluated, however raltegravir concentrations may be decreased with ritonavir coadministration.
Other Agents
Analgesics, Narcotic:
tramadol,
propoxyphene,
methadone,
fentanyl
↑ analgesics




↓ methadone

↑ fentanyl
A dose decrease may be needed for these drugs when co-administered with ritonavir.



Dosage increase of methadone may be considered.

Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with NORVIR.
Anesthetic:
meperidine
↓ meperidine/ ↑ normeperidine (metabolite) Dosage increase and long-term use of meperidine with ritonavir are not recommended due to the increased concentrations of the metabolite normeperidine which has both analgesic activity and CNS stimulant activity (e.g., seizures).
Antialcoholics:
disulfiram/ metronidazole
  Ritonavir formulations contain ethanol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).
Antiarrhythmics:
disopyramide, lidocaine, mexiletine
↑ antiarrhythmics For contraindicated antiarrhythmics [see Contraindications (4)].
Caution is warranted and therapeutic concentration monitoring is recommended for antiarrhythmics when co-administered with ritonavir, if available.
Anticancer Agents:
dasatinib, nilotinib,
venetoclax,
vincristine,
vinblastine
↑ anticancer agents For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when ritonavir is administered concurrently with vincristine or vinblastine.
Clinicians should be aware that if the ritonavir containing regimen is withheld for a prolonged period, consideration should be given to altering the regimen to not include a CYP3A or P-gp inhibitor in order to control HIV-1 viral load.
A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as NORVIR. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions.

Coadministration of venetoclax and NORVIR may increase the risk of tumor lysis syndrome. Refer to the venetoclax prescribing information for dosing instructions.
Anticoagulant:
warfarin
↑↓ warfarin Initial frequent monitoring of the INR during ritonavir and warfarin co-administration is recommended.
Anticoagulant:
rivaroxaban
↑ rivaroxaban Avoid concomitant use of rivaroxaban and ritonavir. Co-administration of ritonavir and rivaroxaban may lead to risk of increased bleeding.
Anticonvulsants:
carbamazepine, clonazepam, ethosuximide
↑ anticonvulsants A dose decrease may be needed for these drugs when co-administered with ritonavir and therapeutic concentration monitoring is recommended for these anticonvulsants, if available.
Anticonvulsants:
divalproex, lamotrigine, phenytoin
↓ anticonvulsants A dose increase may be needed for these drugs when co-administered with ritonavir and therapeutic concentration monitoring is recommended for these anticonvulsants, if available.
Antidepressants:
nefazodone,
selective serotonin
reuptake inhibitors
(SSRIs): e.g.
fluoxetine,
paroxetine,
tricyclics: e.g.
amitriptyline,
nortriptyline
↑ antidepressants A dose decrease may be needed for these drugs when co-administered with ritonavir.
Antidepressant:
bupropion
↓ bupropion
↓ active metabolite, hydroxybupropion
Patients receiving ritonavir and bupropion concurrently should be monitored for an adequate clinical response to bupropion.
Antidepressant:
desipramine
↑ desipramine Dosage reduction and concentration monitoring of desipramine is recommended.
Antidepressant:
trazodone
↑ trazodone Adverse events of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and NORVIR. A lower dose of trazodone should be considered.
Antiemetic:
dronabinol
↑ dronabinol A dose decrease of dronabinol may be needed when co-administered with ritonavir.
Antifungals:
ketoconazole
itraconazole
voriconazole
↑ ketoconazole
↑ itraconazole
↓ voriconazole
For contraindicated antifungals, [see Contraindications (4)].
High doses of ketoconazole or itraconazole (greater than 200 mg per day) are not recommended.

Co-administration of voriconazole and ritonavir doses of 400 mg every 12 hours or greater is contraindicated [see Contraindications (4)]. Co-administration of voriconazole and ritonavir 100 mg should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole.
Anti-gout:
colchicine
↑ colchicine Concomitant administration with colchicine is contraindicated in patients with renal and/or hepatic impairment [see Contraindications (4)].
For patients with normal renal or hepatic function:

Treatment of gout flares-co-administration of colchicine in patients on ritonavir: 0.6 mg (one tablet) for one dose, followed by 0.3 mg (half tablet) one hour later. Dose to be repeated no earlier than three days.

Prophylaxis of gout flares-co-administration of colchicine in patients on ritonavir: If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.

Treatment of familial Mediterranean fever (FMF)-co-administration of colchicine in patients on ritonavir: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Anti-infective:
clarithromycin
↑ clarithromycin For patients with renal impairment, adjust clarithromycin dose as follows:
For patients with CLCR 30 to 60 mL per min the dose of clarithromycin should be reduced by 50%. For patients with CLCR less than 30 mL per min the dose of clarithromycin should be decreased by 75%. No dose adjustment for patients with normal renal function is necessary.
Antimycobacterial:
bedaquiline
↑ bedaquiline Bedaquiline should only be used with ritonavir if the benefit of co-administration outweighs the risk.
Antimycobacterial:
rifabutin
↑ rifabutin and rifabutin metabolite Dosage reduction of rifabutin by at least three-quarters of the usual dose of 300 mg per day is recommended (e.g., 150 mg every other day or three times a week). Further dosage reduction may be necessary.
Antimycobacterial:
rifampin
↓ ritonavir May lead to loss of virologic response. Alternate antimycobacterial agents such as rifabutin should be considered.
Antiparasitic:
atovaquone
↓ atovaquone Clinical significance is unknown; however, increase in atovaquone dose may be needed.
Antiparasitic:
quinine
↑ quinine A dose decrease of quinine may be needed when co-administered with ritonavir.
Antipsychotics:
perphenazine,
risperidone,
thioridazine
↑ antipsychotics For contraindicated antipsychotics, [see Contraindications (4)].
A dose decrease may be needed for these drugs when co-administered with ritonavir.
Antipsychotics:
quetiapine
↑ quetiapine Initiation of NORVIR in patients taking quetiapine:

Consider alternative antiretroviral therapy to avoid increases in quetiapine exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring.

Initiation of quetiapine in patients taking NORVIR:

Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.
β-Blockers:
metoprolol, timolol
↑ beta-blockers Caution is warranted and clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when co-administered with ritonavir.
Bronchodilator:
theophylline
↓ theophylline Increased dosage of theophylline may be required; therapeutic monitoring should be considered.
Calcium channel blockers:
diltiazem, nifedipine, verapamil
↑ calcium channel blockers Caution is warranted and clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when co-administered with ritonavir.
Digoxin ↑ digoxin Concomitant administration of ritonavir with digoxin may increase digoxin levels. Caution should be exercised when co-administering ritonavir with digoxin, with appropriate monitoring of serum digoxin levels.
Endothelin receptor antagonists: bosentan ↑ bosentan Co-administration of bosentan in patients on ritonavir:

In patients who have been receiving ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

Co-administration of ritonavir in patients on bosentan:

Discontinue use of bosentan at least 36 hours prior to initiation of ritonavir.

After at least 10 days following the initiation of ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Hepatitis C direct acting antiviral:
simeprevir
↑simeprevir It is not recommended to co-administer ritonavir with simeprevir.
HMG-CoA Reductase Inhibitor:
atorvastatin
rosuvastatin
↑ atorvastatin

↑ rosuvastatin
For contraindicated HMG-CoA reductase inhibitors, [see Contraindications (4)].
Titrate atorvastatin and rosuvastatin dose carefully and use the lowest necessary dose.
If NORVIR is used with another protease inhibitor, see the complete prescribing information for the concomitant protease inhibitor for details on co-administration with atorvastatin and rosuvastatin.
Immunosuppressants:
cyclosporine,
tacrolimus,
sirolimus
(rapamycin)
↑ immunosuppressants Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with ritonavir.
Systemic/Inhaled/
Nasal/Ophthalmic
Corticosteroids:
e.g., betamethasone
budesonide
ciclesonide
dexamethasone
fluticasone
methylprednisolone
mometasone
prednisone
triamcinolone
↑ glucocorticoids Coadministration with corticosteroids whose exposures are significantly increased by strong CYP3A inhibitors can increase the risk for Cushing’s syndrome and adrenal suppression.

Alternative corticosteroids including beclomethasone and prednisolone (whose PK and/or PD are less affected by strong CYP3A inhibitors relative to other studied steroids) should be considered, particularly for long-term use.
Long-acting beta-adrenoceptor agonist: salmeterol ↑ salmeterol Concurrent administration of salmeterol and ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Oral Contraceptives or Patch Contraceptives:
ethinyl estradiol
↓ ethinyl estradiol Alternate methods of contraception should be considered.
PDE5 Inhibitors:
avanafil
sildenafil,
tadalafil,
vardenafil
↑ avanafil
↑ sildenafil
↑ tadalafil
↑ vardenafil
For contraindicated PDE5 inhibitors, [see Contraindications (4)].
Do not use ritonavir with avanafil because a safe and effective avanafil dosage regimen has not been established.

Particular caution should be used when prescribing sildenafil, tadalafil or vardenafil in patients receiving ritonavir. Coadministration of ritonavir with these drugs may result in an increase in PDE5 inhibitor associated adverse events, including hypotension, syncope, visual changes, and prolonged erection.

Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH):

Sildenafil (Revatio®) is contraindicated [see Contraindications (4)].

The following dose adjustments are recommended for use of tadalafil (Adcirca®) with ritonavir:

Co-administration of ADCIRCA in patients on ritonavir: In patients receiving ritonavir for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Co-administration of ritonavir in patients on ADCIRCA: Avoid use of ADCIRCA during the initiation of ritonavir. Stop ADCIRCA at least 24 hours prior to starting ritonavir. After at least one week following the initiation of ritonavir, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Use of PDE5 inhibitors for the treatment of erectile dysfunction:

It is recommended not to exceed the following doses: Sildenafil: 25 mg every 48 hours Tadalafil: 10 mg every 72 hours Vardenafil: 2.5 mg every 72 hours
Use with increased monitoring for adverse events.

Sedative/hypnotics:
buspirone, clorazepate, diazepam, estazolam, flurazepam, zolpidem
↑ sedative/hypnotics A dose decrease may be needed for these drugs when co-administered with ritonavir.
Sedative/hypnotics: Parenteral midazolam
↑ midazolam For contraindicated sedative/hypnotics, [see Contraindications (4)].
Co-administration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered.
Stimulant:
methamphetamine
↑ methamphetamine Use with caution. A dose decrease of methamphetamine may be needed when co-administered with ritonavir.


Table name:
Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin,
heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole,
prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen,
ibuprofen, indomethacin, ketoprofen,
ketorolac, mefenamic acid, naproxen,
oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone.


Table name:
DRUG DESCRIPTION OF INTERACTION
Sulfonylureas Hypoglycemia potentiated.
Methotrexate Decreases tubular reabsorption; clinical toxicityfrom methotrexate can result.
Oral Anticoagulants Increased bleeding.


Table name:
Digoxin concentrations increased greater than 50%
Digoxin Serum
Concentration

Increase
Digoxin AUC
Increase
Recommendations
Amiodarone 70% NA Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30 to 50% or by modifying the dosing frequency and continue monitoring.
Captopril 58% 39%
Clarithromycin NA 70%
Dronedarone NA 150%
Gentamicin 129 to 212% NA
Erythromycin 100% NA
Itraconazole 80% NA
Lapatinib NA 180%
Propafenone NA 60 to 270%
Quinidine 100% NA
Ranolazine 50% NA
Ritonavir NA 86%
Telaprevir 50% 85%
Tetracycline 100% NA
Verapamil 50 to 75% NA
Digoxin concentrations increased less than 5 0 %
Atorvastatin 22% 15% Measure serum digoxin concentrations before initiating
concomitant drugs. Reduce digoxin concentrations by decreasing the
dose by approximately 15 to 30% or by modifying the dosing frequency and continue monitoring.
Carvedilol 16% 14%
Conivaptan 33% 43%
Diltiazem 20% NA
Indomethacin 40% NA
Nefazodone 27% 15%
Nifedipine 45% NA
Propantheline 24% 24%
Quinine NA 33%
Rabeprazole 29% 19%
Saquinavir 27% 49%
Spironolactone 25% NA
Telmisartan 20 to 49% NA
Ticagrelor 31% 28%
Tolvaptan 30% 20 %
Trimethoprim 22 to 28% NA
Digoxin concentrations increased, but magnitude is unclear
Alprazolam, azithromycin, cyclosporine, diclofenac, diphenoxylate, epoprostenol, esomeprazole, ibuprofen, ketoconazole, lansoprazole, metformin, omeprazole Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin concentrations decreased
Acarbose, activated charcoal, albuterol, antacids, certain cancer chemotherapy or radiation therapy, cholestyramine, colestipol, extenatide, kaolin-pectin, meals high in bran, metoclopramide, miglitol, neomycin, penicillamine, phenytoin, rifampin, St. John’s Wort, sucralfate and sulfasalazine Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20 to 40 % as necessary.


Table name:
Table 1: Drugs that may have their plasma concentrations increased by itraconazole
Drug Class Contraindicated Not Recommended Use with Caution Comments
Under no circumstances is the drug to be coadministered with itraconazole, and up to two weeks after discontinuation of treatment with itraconazole. It is recommended that the use of the drug be avoided during and up to two weeks after discontinuation of treatment with itraconazole, unless the benefits outweigh the potentially increased risks of side effects. If coadministration cannot be avoided, clinical monitoring for signs or symptoms of increased or prolonged effects or side effects of the interacting drug is recommended, and its dosage be reduced or interrupted as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured. The label of the coadministered drug should be consulted for information on dose adjustment and adverse effects. Careful monitoring is recommended when the drug is coadministered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of the interacting drug, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured. The label of the coadministered drug should be consulted for information on dose adjustment and adverse effects.
Alpha Blockers tamsulosin
Analgesics methadone alfentanil, buprenorphine IV and sublingual, fentanyl, oxycodone, sufentanil Methadone: The potential increase in plasma concentrations of methadone when coadministered with itraconazole may increase the risk of serious cardiovascular events including QTc prolongation and torsade de pointes. Fentanyl: The potential increase in plasma concentrations of fentanyl when coadministered with itraconazole may increase the risk of potentially fatal respiratory depression. Sufentanil: No human pharmacokinetic data of an interaction with itraconazole are available. In vitro data suggest that sufentanil is metabolized by CYP3A4 and so potentially increased sufentanil plasma concentrations would be expected when coadministered with itraconazole.
Antiarrhythmics disopyramide, dofetilide, dronedarone, quinidine digoxin Disopyramide, dofetilide, dronedarone, quinidine: The potential increase in plasma concentrations of these drugs when coadministered with itraconazole may increase the risk of serious cardiovascular events including QTc prolongation.
Antibacterials telithromycin, in subjects with severe renal impairment or severe hepatic impairment rifabutin telithromycin Telithromycin: The potential increase in plasma concentrations of telithromycin in subjects with severe renal impairment or severe hepatic impairment, when coadministered with itraconazole may increase the risk of serious cardiovascular events including QT prolongation and torsade de pointes. Rifabutin: See also under ‘Drugs that may decrease itraconazole plasma concentrations’.
Anticoagulants and Antiplatelet Drugs ticagrelor apixaban, rivaroxaban coumarins, cilostazol, dabigatran Ticagrelor: The potential Increase in plasma concentrations of ticagrelor may increase the risk of bleeding. Coumarins: Itraconazole may enhance the anticoagulant effect of coumarin-like drugs, such as warfarin.
Anticonvulsants carbamazepine Carbamazepine: In vivo studies have demonstrated an increase in plasma carbamazepine concentrations in subjects concomitantly receiving ketoconazole. Although there are no data regarding the effect of itraconazole on carbamazepine metabolism, because of the similarities between ketoconazole and itraconazole, concomitant administration of itraconazole and carbamazepine may inhibit the metabolism of carbamazepine. See also under ‘Drugs that may decrease itraconazole plasma concentrations’.
Antidiabetics repaglinide, saxagliptin
Antihelmintics and Antiprotozoals praziquantel
Antimigraine Drugs ergot alkaloids, such as dihydroergotamine, ergometrine (ergonovine), ergotamine, methylergometrine (methylergonovine) eletriptan Ergot Alkaloids: The potential increase in plasma concentrations of ergot alkaloids when coadministered with itraconazole may increase the risk of ergotism, ie. a risk for vasospasm potentially leading to cerebral ischemia and/or ischemia of the extremities.
Antineoplastics irinotecan axitinib, dabrafenib, dasatinib, ibrutinib, nilotinib, sunitinib bortezomib, busulphan, docetaxel, erlotinib, imatinib, ixabepilone, lapatinib, ponatinib, trimetrexate, vinca alkaloids Irinotecan: The potential increase in plasma concentrations of irinotecan when coadministered with itraconazole may increase the risk of potentially fatal adverse events.
Antipsychotics, Anxiolytics and Hypnotics lurasidone, oral midazolam, pimozide, triazolam alprazolam, aripiprazole, buspirone, diazepam, haloperidol, midazolam IV, perospirone, quetiapine, ramelteon, risperidone Midazolam, triazolam: Coadministration of itraconazole and oral midazolam, or triazolam may cause several-fold increases in Plasma concentrations of these drugs. This may potentiate and prolong hypnotic and sedative effects, especially with repeated dosing or chronic administration of these agents. Pimozide: The potential increase in plasma concentrations of pimozide when coadministered with itraconazole may increase the risk of serious cardiovascular events including QTc prolongation and torsade de pointes.
Antivirals simeprevir maraviroc, indinavir, ritonavir, saquinavir Indinavir, ritonavir: See also under ‘Drugs that may increase itraconazole plasma concentrations’.
Beta Blockers nadolol
Calcium Channel Blockers felodipine, nisoldipine other dihydropyridines, verapamil Calcium channel blockers can have a negative inotropic effect which may be additive to those of itraconazole. The potential increase in plasma concentrations of calcium channel blockers when co-administered with itraconazole may increase the risk of congestive heart failure. Dihydropyridines: Concomitant administration of itraconazole may cause several-fold increases inplasma concentrations of dihydropyridines. Edema has been reported in patients concomitantly receiving itraconazole and dihydropyridine calcium channel blockers.
Cardiovascular Drugs, Miscellaneous ranolazine aliskiren, sildenafil, for the treatment of pulmonary hypertension bosentan, riociguat Ranolazine: The potential increase in plasma concentrations of ranolazine when coadministered with itraconazole may increase the risk of serious cardiovascular events including QTc prolongation.
Diuretics eplerenone Eplerenone: The potential increase in plasma concentrations of eplerenone when coadministered with itraconazole may increase the risk of hyperkalemia and hypotension.
Gastrointestinal Drugs cisapride aprepitant Cisapride: The potential increase in plasma concentrations of cisapride when coadministered with itraconazole may increase the risk of serious cardiovascular events including QTc prolongation.
Immunosuppressants everolimus, temsirolimus budesonide, ciclesonide, cyclosporine, dexamethasone, fluticasone, methylprednisolone, rapamycin (also known as sirolimus), tacrolimus
Lipid Regulating Drugs lovastatin, simvastatin atorvastatin The potential increase in plasma concentrations of atorvastatin, lovastatin, and simvastatin when coadministered with itraconazole may increase the risk of skeletal muscle toxicity, including rhabdomyolysis.
Respiratory Drugs salmeterol
Urological Drugs fesoterodine, in subjects with moderate to severe renal impairment, or moderate to severe hepatic impairment, solifenacin, in subjects with severe renal impairment or moderate to severe hepatic impairment darifenacin, vardenafil fesoterodine. oxybutynin, sildenafil, for the treatment of erectile dysfunction, solifenacin, tadalafil, tolterodine Fesoterodine: The potential increase in plasma concentrations of the fesoterodine active metabolite may be greater in subjects with moderate to severe renal impairment, or moderate to severe hepatic impairment, which may lead to an increased risk of adverse reactions. Solifenacin: The potential increase in plasma concentrations of solifenacin in subjects with severe renal impairment or moderate to severe hepatic impairment, when coadministered with itraconazole may increase the risk of serious cardiovascular events including QT prolongation.
Other colchicine, in subjects with renal or hepatic impairment colchicine, conivaptan, tolvaptan cinacalcet Colchicine: The potential increase in plasma concentrations of colchicine when coadministered with itraconazole may increase the risk of potentially fatal adverse events. Conivaptan and Tolvaptan: A safe and effective dose of either conivaptan or tolvaptan has not been established when coadministered with itraconazole.


Table name:
Interacting Drug
Interaction
Theophylline
Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin
Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents
Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin
Monitor phenytoin level (7)
Methotrexate
Monitor for methotrexate toxicity (7)
Cyclosporine
May increase serum creatinine. Monitor serum creatinine (7)
Multivalent cation- containing products including antacids, metal cations or didanosine
Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin (7)


Table name:
Drugs That Interfere with Hemostasis
Clinical Impact: • Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of naproxen or naproxen sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: Concomitant use of naproxen or naproxen sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen or naproxen sodium is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE-inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: • During concomitant use of naproxen or naproxen sodium and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of naproxen or naproxen sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen or naproxen sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact: The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of naproxen or naproxen sodium and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen or naproxen sodium and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of naproxen or naproxen sodium and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of naproxen or naproxen sodium and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of naproxen or naproxen sodium and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of naproxen or naproxen sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of naproxen or naproxen sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact: Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention: Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen or naproxen sodium is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed release tablets are not recommended.
Cholestyramine
Clinical Impact: Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention: Concomitant administration of cholestyramine with naproxen or naproxen sodium is not recommended.
Probenecid
Clinical Impact: Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention: Patients simultaneously receiving naproxen or naproxen sodium and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact: Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention: Patients simultaneously receiving naproxen or naproxen sodium and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.


Table name:
Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
* Change relative to reference
Coadministered Drug
Dosing Schedule
Effect on Active
Moiety (Risperidone + 9-
Hydroxy- Risperidone (Ratio*)
Risperidone Dose
Recommendation

Coadministered Drug
Risperidone
AUC
Cmax

Enzyme (CYP2D6)
Inhibitors





Fluoxetine
20 mg/day 
2 or 3 mg twice
daily
1.4 
1.5
Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine
10 mg/day 
4 mg/day
1.3
-
Re-evaluate dosing. 

20 mg/day 
4 mg/day
1.6
-
Do not exceed 8 mg/day

40 mg/day 
4 mg/day
1.8
-

Enzyme (CYP3A/ PgP inducers) Inducers





Carbamazepine 
573 ± 168 mg/day
3 mg twice daily
0.51 
0.55
Titrate dose upwards.
Do not exceed twice the patient’s usual dose
Enzyme (CYP3A)
Inhibitors





Ranitidine 
150 mg twice daily
1 mg single dose
1.2 
1.4
Dose adjustment not
needed
Cimetidine 
400 mg twice daily
1 mg single dose
1.1 
1.3
Dose adjustment not
needed
Erythromycin 

500 mg four times
daily
1 mg single dose
1.1 
0.94
Dose adjustment not
needed






Other Drugs





Amitriptyline 
50 mg twice daily
3 mg twice daily
1.2 
1.1
Dose adjustment not
needed


Table name:

Figure 7: Mean Standing Systolic Blood Pressure Change from Baseline


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine Do not exceed 10 mg atorvastatin daily
Clarithromycin, itraconazole, HIV protease inhibitors (ritonavir plus saquinavir or lopinavir plus ritonavir) Caution when exceeding doses > 20 mg atorvastatin daily. The lowest dose necessary should be used.


Table name:
Interacting DrugInteracting Drug InteractionInteraction
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products.
Warfarin
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( 7.2)
Antidiabetic agents
Carefully monitor blood glucose ( 5.11, 7.3)


Table name: Gemfibrozil ClopidogrelCyclosporineCYP2C8 and CYP3A4 InhibitorsCYP2C8 and CYP3A4 InducersDrugs That May Increase the Risk of HypoglycemiaDrugs That May Decrease the Blood Glucose Lowering Effect of PRANDINDrugs That May Blunt Signs and Symptoms of Hypoglycemia
 
Clinical Impact: Gemfibrozil significantly increased repaglinide exposures by 8.1 fold [see Clinical Pharmacology (12.3)]
Intervention: Do not administer PRANDIN to patients receiving gemfibrozil [see Contraindications (4)].
 
Clinical Impact: Clopidogrel increased repaglinide exposures by 3.9-5.1 fold [see Clinical Pharmacology (12.3)]
Intervention: Avoid concomitant use of PRANDIN with clopidogrel. If concomitant use can not be avoided, initiate PRANDIN at 0.5 mg before each meal and do not exceed a total daily dose of 4 mg [see DOSAGE AND ADMINISTRATION (2.3)]. Increased frequency of glucose monitoring may be required during concomitant use.
 
Clinical Impact: Cyclosporine increased low dose repaglinide exposures by 2.5 fold [see Clinical Pharmacology (12.3)]
Intervention: Daily maximum PRANDIN dose should be limited to 6 mg, and increased frequency of glucose monitoring may be required when PRANDIN is co-administered with cyclosporine.
 
Intervention: PRANDIN dose reductions and increased frequency of glucose monitoring may be required when co-administered.
Examples: Drugs that are known to inhibit CYP3A4 include antifungal agents (ketoconazole, itraconazole) and antibacterial agents (clarithromycin, erythromycin). Drugs that are known to inhibit CYP2C8 include trimethoprim, gemfibrozil, montelukast, deferasirox, and clopidiogrel.
 
Intervention: PRANDIN dose increases and increased frequency of glucose monitoring may be required when co-administered.
Examples: Drugs that induce the CYP3A4 and/or 2C8 enzyme systems include rifampin, barbiturates, and carbamezapine
 
Intervention: PRANDIN dose reductions and increased frequency of glucose monitoring may be required when co-administered.
Examples: Antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, nonsteroidal anti-inflammatory agents (NSAIDs), pentoxifylline, pramlintide, propoxyphene, salicylates, somatostatin analogs (e.g., octreotide), and sulfonamide antibiotics
 
Intervention: PRANDIN dose increases and increased frequency of glucose monitoring may be required when co-administered.
Examples: Atypical antipsychotics (e.g., olanzapine and clozapine), calcium channel antagonists, corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones.
 
Intervention: Increased frequency of glucose monitoring may be required when PRANDIN is co-administered with these drugs.
Examples: beta-blockers, clonidine, guanethidine, and reserpine


Table name: Clinical RecommendationStrong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin)Increase plasma naloxegol concentrations and may increase the risk of adverse reactions [see Clinical Pharmacology (12.3) ]Use with strong CYP3A4 inhibitors is contraindicated [see Contraindications (4) ].Moderate CYP3A4 inhibitors (e.g., diltiazem, erythromycin, verapamil)Avoid use with moderate CYP3A4 inhibitors; if unavoidable, decrease the dosage of MOVANTIK to 12.5 mg once daily and monitor for adverse reactions [see Dosage and Administration (2.4) ].Weak CYP3A4 inhibitors (e.g., quinidine, cimetidine)Clinically significant increases in naloxegol concentrations are not expected. No dosage adjustments are necessary. Grapefruit or grapefruit juiceThe effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation dependent. Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain preparation was used (e.g., high dose, double strength) or as a “moderate CYP3A inhibitor” when another preparation was used (e.g., low dose, single strength).Can increase plasma naloxegol concentrations. Avoid consumption of grapefruit or grapefruit juice during treatment with MOVANTIK [see Dosage and Administration (2.1) ].CYP3A4 InducersStrong CYP3A4 inducers (e.g., rifampin, carbamazepine, St. John’s Wort)Significantly decrease plasma naloxegol concentrations and may decrease the efficacy of MOVANTIK [see Clinical Pharmacology (12.3) ].    Use with strong CYP3A4 inducers is not recommended.Other opioid antagonistsPotential for additive effect of opioid receptor antagonism and increased risk of opioid withdrawal.Avoid use of MOVANTIKwith another opioid antagonist.
Table 2. Effects of Other Drugs on MOVANTIK
Concomitant Agent Mechanism of Action
CYP3A4 Inhibitors
Other Drug Interactions


Table name:
Drugs That May Potentiate Renal Dysfunction
Antibiotics Antineoplastics Anti-inflammatory Drugs Gastrointestinal Agents
ciprofloxacin gentamicin tobramycin vancomycin trimethoprim with sulfamethoxazole     melphalan   azapropazon colchicine diclofenac naproxen sulindac       cimetidine ranitidine  
Antifungals
amphotericin B ketoconazole   Immunosuppressives
tacrolimus  
Other Drugs
fibric acid derivatives (e.g., bezafibrate, fenofibrate) methotrexate


Table name:
Clinically significant drug interactions with BUPRENEX.
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see WARNINGS].
Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and other opioids, alcohol.
Inhibitors of CYP3A4
Clinical Impact: The concomitant use of buprenorphine and CYP3A4 inhibitors can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of BUPRENEX is achieved.

After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the buprenorphine plasma concentration will decrease [see CLINICAL PHARMACOLOGY: Pharmacokinetics], potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to buprenorphine.
Intervention: If concomitant use is necessary, consider dosage reduction of BUPRENEX until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals.

If a CYP3A4 inhibitor is discontinued, consider increasing the BUPRENEX dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)
CYP3A4 Inducers
Clinical Impact: The concomitant use of buprenorphine and CYP3A4 inducers can decrease the plasma concentration of buprenorphine [see CLINICAL PHARMACOLOGY: Pharmacokinetics] , potentially resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine.

After stopping a CYP3A4 inducer, as the effects of the inducer decline, the buprenorphine plasma concentration will increase [see CLINICAL PHARMACOLOGY: Pharmacokinetics] , which could increase or prolong both therapeutic effects and adverse reactions and may cause serious respiratory depression.
Intervention: If concomitant use is necessary, consider increasing the BUPRENEX dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.

If a CYP3A4 inducer is discontinued, consider BUPRENEX dosage reduction and monitor for signs of respiratory depression.
Examples: Rifampin, carbamazepine, phenytoin
Serotonergic Drugs
Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue BUPRENEX if serotonin syndrome is suspected.
Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome opioid toxicity (e.g., respiratory depression, coma).
Intervention: The use of BUPRENEX is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples: phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact: May reduce the analgesic effect of BUPRENEX and/or precipitate withdrawal symptoms.
Intervention: Avoid concomitant use.
Examples: butorphanol, nalbuphine, pentazocine
Muscle Relaxants
Clinical Impact: Buprenorphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention: Monitor patients receiving muscle relaxants and BUPRENEX for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of BUPRENEX and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact: The concomitant use of anticholinergic drugs may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when BUPRENEX is used concomitantly with anticholinergic drugs.
Antiretrovirals: Nucleoside reverse transcriptase inhibitors (NRTIs)
Clinical Impact: Nucleoside reverse transcriptase inhibitors (NRTIs) do not appear to induce or inhibit the P450 enzyme pathway, thus no interactions with buprenorphine are expected.
Intervention: None
Antiretrovirals: Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Clinical Impact: Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are metabolized principally by CYP3A4. Efavirenz, nevirapine, and etravirine are known CYP3A inducers, whereas delaviridine is a CYP3A inhibitor. Significant pharmacokinetic interactions between NNRTIs (e.g., efavirenz and delavirdine) and buprenorphine have been shown in clinical studies, but these pharmacokinetic interactions did not result in any significant pharmacodynamic effects.
Intervention: Patients who are on chronic BUPRENEX treatment should have their dose monitored if NNRTIs are added to their treatment regimen.
Examples: efavirenz, nevirapine, etravirine, delavirdine
Antiretrovirals: Protease inhibitors (PIs)
Clinical Impact: Studies have shown some antiretroviral protease inhibitors (PIs) with CYP3A4 inhibitory activity (nelfinavir, lopinavir/ritonavir, ritonavir) have little effect on buprenorphine pharmacokinetic and no significant pharmacodynamic effects. Other PIs with CYP3A4 inhibitory activity (atazanavir and atazanavir/ritonavir) resulted in elevated levels of buprenorphine and norbuprenorphine, and patients in one study reported increased sedation. Symptoms of opioid excess have been found in post-marketing reports of patients receiving buprenorphine and atazanavir with and without ritonavir concomitantly.
Intervention: Monitor patients taking BUPRENEX and atazanavir with and without ritonavir, and dose reduction of BUPRENEX may be warranted.
Examples: atazanavir, ritonavir


Table name:
CYP2C19 or CYP3A4 Inducers
Clinical Impact:   Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology (12.3)].
Intervention:   St. John’s Wort, rifampin: Avoid concomitant use with omeprazole [see Warnings and Precautions (5.9)]. Ritonavir-containing products: see prescribing information for specific drugs.
 CYP2C19 or CYP3A4 Inhibitors
Clinical Impact: Increased exposure of omeprazole [see Clinical Pharmacology (12.3)].
Intervention:   Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered. See prescribing information for voriconazole.


Table name:
Calcium Channel BIockers Antifungals Antibiotics Glucocorticoids Other Drugs
diltiazem
nicardipine
verapamil
fluconazole
itraconazole
ketoconazole
voriconazole
azithromycin
clarithromycin
erythromycin
quinupristin/dalfopristin
methylprednisolone allopurinol
amiodarone
bromocriptine
colchicine
danazol
imatinib
metoclopramide
nefazodone
oral contraceptives


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 4: Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table 5 for Magnitude of Interaction.
Drug Name Effect on Concentration of Nevirapine or Concomitant Drug Clinical Comment
HIV Antiviral Agents: Protease Inhibitors (PIs)
Atazanavir/RitonavirThe interaction between immediate-release nevirapine and the drug was evaluated in a clinical study. The results of drug interaction studies with immediate-release nevirapine are expected to also apply to nevirapine extended-release tablets. ↓ Atazanavir
↑ Nevirapine
Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures.
Fosamprenavir ↓ Amprenavir
↑ Nevirapine
Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.
Fosamprenavir/Ritonavir ↓ Amprenavir
↑ Nevirapine
No dosing adjustments are required when nevirapine is co-administered with 700 mg/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied.
Indinavir ↓ Indinavir The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established.
Lopinavir/Ritonavir ↓ Lopinavir Dosing in adult patients: A dose adjustment of lopinavir/ritonavir to 500 mg/125 mg tablets twice daily or 533 mg/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. Dosing in pediatric patients: Please refer to the Kaletra® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.
Nelfinavir ↓ Nelfinavir M8 Metabolite
↓ Nelfinavir Cmin
The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established.
Saquinavir/Ritonavir The interaction between nevirapine and saquinavir/ritonavir has not been evaluated The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz ↓ Efavirenz The appropriate doses of these combinations with respect to safety and efficacy have not been established.
Delavirdine
Etravirine
Rilpivirine
Plasma concentrations may be altered. Nevirapine should not be co-administered with another NNRTI as this combination has not been shown to be beneficial.
Hepatitis C Antiviral Agents
Boceprevir Plasma concentrations of boceprevir may be decreased due to induction of CYP3A4/5 by nevirapine. Nevirapine and boceprevir should not be co-administered because decreases in boceprevir plasma concentrations may result in a reduction in efficacy.
Telaprevir Plasma concentrations of telaprevir may be decreased due to induction of CYP3A4 by nevirapine and plasma concentrations of nevirapine may be increased due to inhibition of CYP3A4 by telaprevir. Nevirapine and telaprevir should not be co-administered because changes in plasma concentrations of nevirapine, telaprevir, or both may result in a reduction in telaprevir efficacy or an increase in nevirapine-associated adverse events.
Other Agents
Analgesics:
Methadone

↓ Methadone

Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Antiarrhythmics:
Amiodarone, disopyramide, lidocaine
Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Antibiotics:
Clarithromycin

↓ Clarithromycin
↑ 14-OH clarithromycin

Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.
Rifabutin ↑ Rifabutin Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.
Rifampin ↓ Nevirapine Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Anticonvulsants:
Carbamazepine, clonazepam, ethosuximide
Plasma concentrations of nevirapine and the anticonvulsant may be decreased. Use with caution and monitor virologic response and levels of anticonvulsants.
Antifungals:
Fluconazole

↑ Nevirapine

Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events.
Ketoconazole ↓ Ketoconazole Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.
Itraconazole ↓ Itraconazole Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug.
Antithrombotics:
Warfarin

Plasma concentrations may be increased.

Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.
Calcium channel blockers:
Diltiazem, nifedipine, verapamil

Plasma concentrations may be decreased.

Appropriate doses for these combinations have not been established.
Cancer chemotherapy:
Cyclophosphamide

Plasma concentrations may be decreased.

Appropriate doses for this combination have not been established.
Ergot alkaloids:
Ergotamine

Plasma concentrations may be decreased.

Appropriate doses for this combination have not been established.
Immunosuppressants:
Cyclosporine, tacrolimus, sirolimus

Plasma concentrations may be decreased.

Appropriate doses for these combinations have not been established.
Motility agents:
Cisapride

Plasma concentrations may be decreased.

Appropriate doses for this combination have not been established.
Opiate agonists:
Fentanyl

Plasma concentrations may be decreased.

Appropriate doses for this combination have not been established.
Oral contraceptives:
Ethinyl estradiol and Norethindrone

↓ Ethinyl estradiol
↓ Norethindrone

Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended.


Table name:
Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) VIAGRA 100 mg
Supine 7.9 (4.6, 11.1)
Standing
4.3 (-1.8,10.3)


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or 
Concomitant Drug
Clinical Comment 
↓= Decreased (induces lamotrigine gluronidation). ↑= Increased (inhibits lamotrigine glucuronidation). ?= Conflicting data.
Estrogen-containing oral 
contraceptive preparations 
containing 30 mcg ethinylestradiol 
and 150 mcg levonorgestrel
↓ lamotrigine



Decreased lamotrigine levels 
approximately 50%.


↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and 
CBZ epoxide
↓ lamotrigine
Addition of carbamazepine decreases lamotrigine 
concentration approximately 40%.
? CBZ epoxide May increase CBZ epoxide levels
Phenobarbital/Primidone ↓ lamotrigine Decreased lamotrigine 
concentration approximately 40%.
Phenytoin (PHT) ↓ lamotrigine Decreased lamotrigine 
concentration approximately 40%
Rifampin ↓ lamotrigine Decreased lamotrigine AUC 
approximately 40%
Valproate ↑ lamotrigine
Increased lamotrigine concentrations slightly 
more than 2-fold.
? valproate Decreased valproate concentrations an average of 
25% over a 3-week period then stabilized in healthy volunteers; 
no change in controlled clinical trials in epilepsy patients.


Table name:
Factors   Dosage Adjustment of aripiprazole
 Known CYP2D6 Poor Metabolizers  Administer half of usual dose
 Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors  Administer a quarter of usual dose
 Strong CYP2D6 or CYP3A4 inhibitors  Administer half of usual dose
 Strong CYP2D6 and CYP3A4 inhibitors  Administer a quarter of usual dose
 Strong CYP3A4 inducers  Double usual dose over 1 to 2 weeks


Table name:
Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol, famotidine nizatidine
systemic and inhaled felodipine norfloxacin
amoxicillin finasteride ofloxacin
ampicillin, hydrocortisone omeprazole
with or without isoflurane prednisone, prednisolone
sulbactam isoniazid ranitidine
atenolol isradipine rifabutin
azithromycin influenza vaccine roxithromycin
caffeine, ketoconazole sorbitol
  dietary ingestion lomefloxacin (purgative doses do not
cefaclor mebendazole inhibit theophylline
co-trimoxazole medroxyprogesterone absorption)
(trimethoprim and methylprednisolone sucralfate
sulfamethoxazole) metronidazole terbutaline, systemic
diltiazem metoprolol terfenadine
dirithromycin nadolol tetracycline
enflurane nifedipine tocainide


Table name:
Table 2 Clinically Significant Drug Interactions with Indomethacin
Drugs That Interfere with Hemostasis
Clinical Impact: Indomethacin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of indomethacin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of indomethacin extended-release capsules with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].
Intervention: Concomitant use of indomethacin extended-release capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. Indomethacin extended-release capsules are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: During concomitant use of indomethacin extended-release capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of indomethacin extended-release capsules and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. It has been reported that the addition of triamterene to a maintenance schedule of indomethacin extended-release capsules resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin extended-release capsules and triamterene should not be administered together. Both indomethacin extended-release capsules and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin extended-release capsules and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently.
Intervention: Indomethacin and triamterene should not be administered together. During concomitant use of indomethacin extended-release capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects. Be aware that indomethacin and potassium-sparing diuretics may both be associated with increased serum potassium levels [see Warnings and Precautions (5.6)].
Digoxin
Clinical Impact: The concomitant use of indomethacin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of indomethacin extended-release capsules and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of indomethacin extended-release capsules and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of indomethacin extended-release capsules and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of indomethacin extended-release capsules and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of indomethacin extended-release capsules and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)]. Combined use with diflunisal may be particularly hazardous because diflunisal causes significantly higher plasma levels of indomethacin [see Clinical Pharmacology (12.3)]. In some patients, combined use of indomethacin and diflunisal has been associated with fatal gastrointestinal hemorrhage.
Intervention: The concomitant use of indomethacin with other NSAIDs or salicylates, especially diflunisal, is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of indomethacin extended-release capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of indomethacin extended-release capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Probenecid
Clinical Impact: When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased.
Intervention: During the concomitant use of indomethacin extended-release capsules and probenecid, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect. When increases in the dose of indomethacin are made, they should be made carefully and in small increments.


Table name:
Drugs That Interfere with Hemostasis
Clinical Impact: • Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.  
· Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of naproxen sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].
Intervention: • Concomitant use of naproxen sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)].
• Naproxen sodium tablets are not substitutes for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).
• In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: • During concomitant use of naproxen sodium and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.
• During concomitant use of naproxen sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)].
• When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Digoxin
Clinical Impact: The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin
Intervention: During concomitant use of naproxen sodium and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen sodium and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of naproxen sodium and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of naproxen sodium and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of naproxen sodium and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention: The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of naproxen sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: · During concomitant use of naproxen sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.
· NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.
· In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.  
Antacids and Sucralfate  
Clinical Impact: Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention: Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen sodium tablets are not recommended.
Cholestyramine
Clinical Impact: Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention: Concomitant administration of cholestyramine with naproxen sodium tablet is not recommended.
Probenecid
Clinical Impact: Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention: Patients simultaneously receiving naproxen sodium tablets and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact: Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention: Patients simultaneously receiving naproxen sodium and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.


Table name:
Table 2: Clinically Significant Drug Interactions with Mefenamic Acid
Drugs  That  Interfere  with  Hemostasis
Clinical  Impact :
•  Mefenamic acid and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of mefenamic acid and anticoagulants have an increased risk of serious 
bleeding compared to the use of either drug alone. 
•  Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake 
and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention
Monitor patients with concomitant use of mefenamic acid with anticoagulants (e.g.,warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin  norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin 
Clinical  Impact
Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study,  the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention
Concomitant use of mefenamic acid and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Mefenamic acid is not a substitute for low dose aspirin for cardiovascular protection.
ACE  Inhibitors Angiotensin  Receptor  Blockers and  Beta - Blockers 
Clinical  Impact
•  NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). 
•  In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration 
of renal function, including possible acute renal failure. These effects are usually reversible. 
Intervention :
•  During concomitant use of mefenamic acid and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. •  During concomitant use of mefenamic acid and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). • When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics 
Clinical  Impact
Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. 
This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. 
Intervention 

During concomitant use of mefenamic acid with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects  (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin 
Clinical  Impact
The concomitant use of mefenamic acid with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. 
Intervention
During concomitant use of mefenamic acid and digoxin, monitor serum digoxin levels. 
Lithium 
Clinical  Impact
NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearanceThe mean minimum lithium concentration increased 15%, and the renal clearance decreased by 
approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. 
Intervention
During concomitant use of mefenamic acid and lithium, monitor patients for signs of lithium toxicity. 
Methotrexate 
Clinical  Impact
Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). 
Intervention
During concomitant use of mefenamic acid and methotrexate, monitor patients for methotrexate toxicity. 
Cyclosporine 
Clinical  Impact
Concomitant use of mefenamic acid and cyclosporine may increase cyclosporine’s nephrotoxicity. 
Intervention
During concomitant use of mefenamic acid and cyclosporine, monitor patients for signs of worsening renal function. 
NSAIDs  and  Salicylates 
Clinical  Impact
Concomitant use of mefenamic acid with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy  (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention
The concomitant use of mefenamic acid with other NSAIDs or salicylates is not recommended. 
Pemetrexed 
Clinical  Impact
Concomitant use of mfenamic acid and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). 
Intervention
During concomitant use of mefenamic acid and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.
NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. 
In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at 
least five days before, the day of, and two days following pemetrexed administration. 
Antacid 
Clinical  Impact
In a single dose study (n= 6), ingestion of an antacid containing 1.7-gram of magnesium hydroxide with 500-mg of mefenamic acid increased the Cm a x and AUC of mefenamic acid by 125% and 36%,
 respectively.
Intervention
Concomitant use of mefenamic acid and antacids is not generally recommended because of possible increased adverse events. 


Table name:
Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) VIAGRA 25 mg
Supine 7.4 (-0.9, 15.7)
Standing 6.0 (-0.8, 12.8)


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
 Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)  Avoid atorvastatin
 HIV protease inhibitor (lopinavir plus ritonavir)  Use with caution and lowest dose necessary
 Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)  Do not exceed 20 mg atorvastatin daily
 HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
 Do not exceed 40 mg atorvastatin daily


Table name:
 Interacting Agents  Prescribing Recommendations
 Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)  Avoid atorvastatin
 HIV protease inhibitor (lopinavir plus ritonavir)  Use with caution and lowest dose necessary
 Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)  Do not exceed 20 mg atorvastatin daily
 HIV protease inhibitors (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
 Do not exceed 40 mg atorvastatin daily


Table name:
 Interacting Agents  Prescribing Recommendations 
 Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone  Avoid simvastatin 
 Gemfibrozil, cyclosporine,danazol   Do not exceed 10 mg simvastatindaily 
 Amiodarone, verapamil  Do not exceed 20 mg simvastatin daily 
 Diltiazem  Do not exceed 40 mg simvastatin daily
 Grapefruit juice  Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Interacting DrugInteracting Drug InteractionInteraction
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products ( 2.4, 7.1)
Warfarin
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( 7.2)
Antidiabetic agents
Carefully monitor blood glucose ( 5.12, 7.3)


Table name:
 Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
  Interacting Agents   Prescribing Recommendations
  Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)  Avoid atorvastatin
 HIV protease inhibitor (lopinavir plus ritonavir)  Use with caution and lowest dose necessary
  Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)  Do not exceed 20 mg atorvastatin daily
 HIV protease inhibitor (nelfinavir)
Hepatitis C Protease inhibitor (boceprevir)
 Do not exceed 40 mg atorvastatin daily


Table name:
Interacting Agents
Prescribing Recommendation
Strong CYP3A4 inhibitors
(e.g,. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir nefazodone, cobicistat­containing products), gemfibrozil, cyclosporine, danazol
 
Contraindicated with simvastatin
 
Verapamil, diltiazem, dronedarone
Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine
Do not exceed 20 mg simvastatin daily
Lomitapide
For patients with HoFH, do not exceed 20 mg simvastatin daily*
Grapefruit juice
Avoid grapefruit juice


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide

Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide






Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T and T levels and increase TSH, although all values remain within normal limits in most patients. 4 3
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate










Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
  Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration   Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen





Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid


Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)





Administration of these agents with levothyroxine results in an initial transient increase in FT . Continued administration results in a decrease in serum T and normal FT and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T and T to TBG and transthyretin. An initial increase in serum FT , is followed by return of FT to normal levels with sustained therapeutic serum salicylate concentrations, although total-T levels may decrease by as much as 30%. 4 4 4 4 3 4 4 4
  Drugs that may alter T 4 and T 3 metabolism
  Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin


Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. 4
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)




Administration of these enzyme inhibitors decrease the peripheral conversion of T to T , leading to decreased T levels. However, serum T levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T and T levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T concentrations by 30% with minimal change in serum T levels. However, long-term glucocorticoid therapy may result in slightly decreased T and T levels due to decreased TBG production (see above). 4 3 3 4 3 4 3 4 3 4
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives

Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)


Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin




Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2

Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin

Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of I, I, and Tc. 123 131 99m
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics









These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 1: Drugs that may have their plasma concentrations increased by itraconazole
Drug Class Contraindicated Not Recommended Use with Caution Comments
Under no circumstances is the drug to be coadministered with itraconazole, and up to two weeks after discontinuation of treatment with itraconazole. It is recommended that the use of the drug be avoided during and up to two weeks after discontinuation of treatment with itraconazole, unless the benefits outweigh the potentially increased risks of side effects. If coadministration cannot be avoided, clinical monitoring for signs or symptoms of increased or prolonged effects or side effects of the interacting drug is recommended, and its dosage be reduced or interrupted as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured. The label of the coadministered drug should be consulted for information on dose adjustment and adverse effects. Careful monitoring is recommended when the drug is coadministered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of the interacting drug, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured. The label of the coadministered drug should be consulted for information on dose adjustment and adverse effects.
Alpha Blockers tamsulosin
Analgesics methadone alfentanil,
buprenorphine IV and sublingual,
fentanyl,
oxycodone,
sufentanil
Methadone: The potential increase in plasma concentrations of methadone when coadministered with SPORANOX® may increase the risk of serious cardiovascular events including QTc prolongation and torsade de pointes.
Fentanyl: The potential increase in plasma concentrations of fentanyl when coadministered with SPORANOX® may increase the risk of potentially fatal respiratory depression.
Sufentanil: No human pharmacokinetic data of an interaction with itraconazole are available. In vitro data suggest that sufentanil is metabolized by CYP3A4 and so potentially increased sufentanil plasma concentrations would be expected when coadministered with SPORANOX®.
Antiarrhythmics disopyramide,
dofetilide,
dronedarone,
quinidine
digoxin Disopyramide, dofetilide, dronedarone, quinidine: The potential increase in plasma concentrations of these drugs when coadministered with SPORANOX® may increase the risk of serious cardiovascular events including QTc prolongation.
Antibacterials telithromycin, in subjects with severe renal impairment or severe hepatic impairment rifabutin telithromycin Telithromycin: The potential increase in plasma concentrations of telithromycin in subjects with severe renal impairment or severe hepatic impairment, when coadministered with SPORANOX® may increase the risk of serious cardiovascular events including QT prolongation and torsade de pointes.
Rifabutin: See also under 'Drugs that may decrease itraconazole plasma concentrations'.
Anticoagulants and Antiplatelet Drugs ticagrelor apixaban,
rivaroxaban
coumarins,
cilostazol,
dabigatran
Ticagrelor: The potential increase in plasma concentrations of ticagrelor may increase the risk of bleeding.
Coumarins: SPORANOX® may enhance the anticoagulant effect of coumarin-like drugs, such as warfarin.
Anticonvulsants carbamazepine Carbamazepine: In vivo studies have demonstrated an increase in plasma carbamazepine concentrations in subjects concomitantly receiving ketoconazole. Although there are no data regarding the effect of itraconazole on carbamazepine metabolism, because of the similarities between ketoconazole and itraconazole, concomitant administration of SPORANOX® and carbamazepine may inhibit the metabolism of carbamazepine. See also under 'Drugs that may decrease itraconazole plasma concentrations'.
Antidiabetics repaglinide,
saxagliptin
Antihelmintics and Antiprotozoals praziquantel
Antimigraine Drugs ergot alkaloids, such as dihydroergotamine,
ergometrine (ergonovine),
ergotamine,
methylergometrine (methylergonovine)
eletriptan Ergot Alkaloids: The potential increase in plasma concentrations of ergot alkaloids when coadministered with SPORANOX® may increase the risk of ergotism, ie. a risk for vasospasm potentially leading to cerebral ischemia and/or ischemia of the extremities.
Antineoplastics irinotecan axitinib,
dabrafenib,
dasatinib,
ibrutinib,
nilotinib,
sunitinib,
trabectedin
bortezomib,
busulphan,
docetaxel,
erlotinib,
gefitinib,
imatinib,
ixabepilone,
lapatinib,
ponatinib,
trimetrexate,
vinca alkaloids
Irinotecan: The potential increase in plasma concentrations of irinotecan when coadministered with SPORANOX® may increase the risk of potentially fatal adverse events.
Antipsychotics, Anxiolytics and Hypnotics lurasidone,
oral midazolam,
pimozide,
triazolam
alprazolam,
aripiprazole,
buspirone,
diazepam,
haloperidol,
midazolam IV,
perospirone,
quetiapine,
ramelteon,
risperidone
Midazolam, triazolam: Coadministration of SPORANOX® and oral midazolam, or triazolam may cause several-fold increases in plasma concentrations of these drugs. This may potentiate and prolong hypnotic and sedative effects, especially with repeated dosing or chronic administration of these agents.
Pimozide: The potential increase in plasma concentrations of pimozide when coadministered with SPORANOX® may increase the risk of serious cardiovascular events including QTc prolongation and torsade de pointes.
Antivirals simeprevir maraviroc,
indinavir,
ritonavir,
saquinavir
Indinavir, ritonavir: See also under 'Drugs that may increase itraconazole plasma concentrations'.
Beta Blockers nadolol
Calcium Channel Blockers felodipine,
nisoldipine
other dihydropyridines,
verapamil
Calcium channel blockers can have a negative inotropic effect which may be additive to those of itraconazole. The potential increase in plasma concentrations of calcium channel blockers when co-administered with SPORANOX® may increase the risk of congestive heart failure.
Dihydropyridines: Concomitant administration of SPORANOX® may cause several-fold increases in plasma concentrations of dihydropyridines. Edema has been reported in patients concomitantly receiving SPORANOX® and dihydropyridine calcium channel blockers.
Cardiovascular Drugs, Miscellaneous Ivabradine,
ranolazine
aliskiren,
sildenafil, for the treatment of pulmonary hypertension
bosentan,
riociguat
Ivabradine: The potential increase in plasma concentrations of ivabradine when coadministered with SPORANOX® may increase the risk of ivabradine-related adverse events, such as atrial fibrillation, bradycardia, sinus arrest and heart block.
Ranolazine: The potential increase in plasma concentrations of ranolazine when coadministered with SPORANOX® may increase the risk of serious cardiovascular events including QTc prolongation.
Diuretics eplerenone Eplerenone: The potential increase in plasma concentrations of eplerenone when coadministered with SPORANOX® may increase the risk of hyperkalemia and hypotension.
Gastrointestinal Drugs cisapride aprepitant Cisapride: The potential increase in plasma concentrations of cisapride when coadministered with SPORANOX® may increase the risk of serious cardiovascular events including QTc prolongation.
Immunosuppressants everolimus,
temsirolimus
budesonide,
ciclesonide,
cyclosporine,
dexamethasone,
fluticasone,
methylprednisolone,
rapamycin (also known as sirolimus),
tacrolimus
Lipid Regulating Drugs lovastatin,
simvastatin
atorvastatin The potential increase in plasma concentrations of atorvastatin, lovastatin, and simvastatin when coadministered with SPORANOX® may increase the risk of skeletal muscle toxicity, including rhabdomyolysis.
Respiratory Drugs salmeterol
Urological Drugs fesoterodine, in subjects with moderate to severe renal impairment, or moderate to severe hepatic impairment,
solifenacin, in subjects with severe renal impairment or moderate to severe hepatic impairment
darifenacin,
vardenafil
fesoterodine.
oxybutynin,
sildenafil, for the treatment of erectile dysfunction,
solifenacin,
tadalafil,
tolterodine
Fesoterodine: The potential increase in plasma concentrations of the fesoterodine active metabolite may be greater in subjects with moderate to severe renal impairment, or moderate to severe hepatic impairment, which may lead to an increased risk of adverse reactions.
Solifenacin: The potential increase in plasma concentrations of solifenacin in subjects with severe renal impairment or moderate to severe hepatic impairment, when coadministered with SPORANOX® may increase the risk of serious cardiovascular events including QT prolongation.
Other colchicine, in subjects with renal or hepatic impairment colchicine,
conivaptan,
tolvaptan
cinacalcet Colchicine: The potential increase in plasma concentrations of colchicine when coadministered with SPORANOX® may increase the risk of potentially fatal adverse events.
Conivaptan and Tolvaptan: A safe and effective dose of either conivaptan or tolvaptan has not been established when coadministered with SPORANOX®.


Table name:
Interacting DrugInteracting Drug InteractionInteraction
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products ( 2.4, 7.1)
Warfarin
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( 7.2)
Antidiabetic agents
Carefully monitor blood glucose ( 5.12, 7.3)


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Table 4. Established and Other Potentially Significant Drug Interactions
↓ = Decreased (induces lamotrigine glucuronidation).
↑ = Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
Concomitant Drug 
Effect on Concentration
of Lamotrigine or
Concomitant Drug
Clinical Comment 
Estrogen-containing oral 
contraceptive preparations
containing 30 mcg 
ethinylestradiol and 150 mcg
levonorgestrel 
↓ lamotrigine 


↓ levonorgestrel 
Decreased lamotrigine levels 
approximately 50%. 

Decrease in levonorgestrel 
component by 19%. 
Carbamazepine and
carbamazepine epoxide 
↓ lamotrigine 


? carbamazepine
  epoxide 
Addition of carbamazepine 
decreases lamotrigine 
concentration approximately 40%. 
May increase carbamazepine
epoxide levels. 
Phenobarbital/Primidone 
↓ lamotrigine 
Decreased lamotrigine 
concentration approximately 40%. 
Phenytoin 
↓ lamotrigine 
Decreased lamotrigine 
concentration approximately 40%. 
Rifampin 
↓ lamotrigine
Decreased lamotrigine 
AUC approximately 40%. 
Valproate 
↑ lamotrigine 


? valproate 
Increased lamotrigine 
concentrations slightly more than 
2-fold. 
Decreased valproate concentrations 
an average of 25% over a 3-week 
period then stabilized in healthy 
volunteers; no change in controlled 
clinical trials in epilepsy patients. 


Table name:
Table 5: Established Drug Interactions Based on Studies with Didanosine Delayed-Release Capsules or Studies with Buffered Formulations of Didanosine and Expected to Occur with Didanosine Delayed-Release Capsules
Drug Effect Clinical Comment
↑ Indicates increase.
↓ Indicates decrease.
a Coadministration of didanosine with food decreases didanosine concentrations. Thus, although not studied, it is possible that coadministration with heavier meals could reduce didanosine concentrations further.

   ganciclovir

   ↑ didanosine concentration

If there is no suitable alternative to ganciclovir, then use in combination with didanosine delayed-release capsules with caution. Monitor for didanosine-
associated toxicity.

   methadone

   ↓ didanosine concentration

If coadministration of methadone and didanosine is necessary, the recommended formulation of didanosine is didanosine delayed-release capsules. Patients
should be closely monitored for adequate clinical response when didanosine delayed-release capsules is coadministered with methadone, including monitoring
for changes in HIV RNA viral load. Do not coadminister methadone with didanosine pediatric powder due to significant decreases in didanosine concentrations.

   nelfinavir

   No interaction 1 hour after didanosine

Administer nelfinavir 1 hour after didanosine delayed-release capsules.

   tenofovir disoproxil fumarate

   ↑ didanosine concentration

A dose reduction of didanosine delayed-release capsules to the following dosage once daily taken together with tenofovir disoproxil fumarate and a light meal
(400 kcalories or less and 20% fat or less) or in the fasted state is recommended.a
250 mg (adults weighing at least 60 kg with creatinine clearance of at least 60 mL/min) 200 mg (adults weighing less than 60 kg with creatinine clearance of at least 60 mL/min) Patients should be monitored for didanosine-associated toxicities and clinical response.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor
(boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Table 2: Drug Interactions: Pharmacokinetic Parameters for Indinavir in the Presence of the Coadministered Drug (See PRECAUTIONS, Table 9 for Recommended Alterations in Dose or Regimen)
Coadministered drug Dose of Coadministered drug (mg) Dose of CRIXIVAN
(mg)
n Ratio (with/without coadministered drug) of Indinavir
Pharmacokinetic Parameters
(90% CI); No Effect = 1.00
Cmax AUC Cmin
All interaction studies conducted in healthy, HIV-negative adult subjects, unless otherwise indicated.
Cimetidine 600 twice daily,
6 days
400 single dose 12 1.07
(0.77, 1.49)
0.98
(0.81, 1.19)
0.82
(0.69, 0.99)
Clarithromycin 500 q12h,
7 days
800 three times
daily, 7 days
10 1.08
(0.85, 1.38)
1.19
(1.00, 1.42)
1.57
(1.16, 2.12)
Delavirdine 400 three times daily 400 three times
daily, 7 days
28 0.64Relative to indinavir 800 mg three times daily alone.
(0.48, 0.86)
No significant change 2.18
(1.16, 4.12)
Delavirdine 400 three times daily 600 three times
daily, 7 days
28 No significant change 1.53
(1.07, 2.20)
3.98
(2.04, 7.78)
EfavirenzStudy conducted in HIV-positive subjects. 600 once daily,
10 days
1000 three times
daily, 10 days
20
After morning dose No significant change 0.67
(0.61, 0.74)
0.61
(0.49, 0.76)
After afternoon dose No significant change 0.63
(0.54, 0.74)
0.48
(0.43, 0.53)
After evening dose 0.71
(0.57, 0.89)
0.54
(0.46, 0.63)
0.43
(0.37, 0.50)
Fluconazole 400 once daily,
8 days
1000 three times daily, 7 days 11 0.87
(0.72, 1.05)
0.76
(0.59, 0.98)
0.90
(0.72, 1.12)
Grapefruit Juice 8 oz. 400 single dose 10 0.65
(0.53, 0.79)
0.73
(0.60, 0.87)
0.90
(0.71, 1.15)
Isoniazid 300 once daily in the morning,
8 days
800 three times daily, 7 days 11 0.95
(0.88, 1.03)
0.99
(0.87, 1.13)
0.89
(0.75, 1.06)
Itraconazole 200 twice daily,
7 days
600 three times
daily, 7 days
12 0.78
(0.69, 0.88)
0.99
(0.91, 1.06)
1.49
(1.28, 1.74)
Ketoconazole 400 once daily,
7 days
600 three times
daily, 7 days
12 0.69
(0.61, 0.78)
0.80
(0.74, 0.87)
1.29
(1.11, 1.51)
400 once daily,
7 days
400 three times
daily, 7 days
12 0.42
(0.37, 0.47)
0.44
(0.41, 0.48)
0.73
(0.62, 0.85)
Methadone 20-60 once daily in the morning,
8 days
800 three times
daily, 8 days
10 See text below for discussion of interaction.
Quinidine 200 single dose 400 single dose 10 0.96
(0.79, 1.18)
1.07
(0.89, 1.28)
0.93
(0.73, 1.19)
Rifabutin 150 once daily in the morning,
10 days
800 three times
daily, 10 days
14 0.80
(0.72, 0.89)
0.68
(0.60, 0.76)
0.60
(0.51, 0.72)
Rifabutin 300 once daily in the morning,
10 days
800 three times
daily, 10 days
10 0.75
(0.61, 0.91)
0.66
(0.56, 0.77)
0.61
(0.50, 0.75)
Rifampin 600 once daily in the morning,
8 days
800 three times
daily, 7 days
12 0.13
(0.08, 0.22)
0.08
(0.06, 0.11)
Not Done
Ritonavir 100 twice daily,
14 days
800 twice
daily, 14 days
10, 16Comparison to historical data on 16 subjects receiving indinavir alone. See text below for discussion of interaction.
Ritonavir 200 twice daily,
14 days
800 twice
daily,14 days
9, 16 See text below for discussion of interaction.
Sildenafil 25 single dose 800 three times daily 6 See text below for discussion of interaction.
St. John's wort
(Hypericum perforatum,
standardized to 0.3 % hypericin)
300 three times daily with meals,
14 days
800 three times daily 8 Not Available 0.46
(0.34, 0.58)95% CI.
0.19
(0.06, 0.33)
Stavudine (d4T) 40 twice daily,
7 days
800 three times
daily, 7 days
11 0.95
(0.80, 1.11)
0.95
(0.80, 1.12)
1.13
(0.83, 1.53)
Trimethoprim/
Sulfamethoxazole
800 Trimethoprim/
160 Sulfamethoxazole q12h, 7 days
400 four times
daily, 7 days
12 1.12
(0.87, 1.46)
0.98
(0.81, 1.18)
0.83
(0.72, 0.95)
Zidovudine 200 three times daily, 7 days 1000 three times
daily, 7 days
12 1.06
(0.91, 1.25)
1.05
(0.86, 1.28)
1.02
(0.77, 1.35)
Zidovudine/
Lamivudine
(3TC)
200/150 three times daily,
7 days
800 three times
daily, 7 days
6, 9Parallel group design; n for indinavir + coadministered drug, n for indinavir alone. 1.05
(0.83, 1.33)
1.04
(0.67, 1.61)
0.98
(0.56, 1.73)


Table name:
Table 18. Summary of Effect of Co-administered Drugs on Exposure to Active Moiety (Risperidone + 9- Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Co-administered Drug  Dosing Schedule  Effect on Active Moeity (Risperidone + 9-Hydroxy-Risperidone (RatioChange relative to reference Risperidone Dose Recommendation 
  Co-administered Drug  Risperidone  AUC  Cmax   
Enzyme (CYP2D6) Inhibitors           
Fluoxetine  20 mg/day  2 or 3 twice daily  1.4  1.5  Re-evaluate dosing. Do not exceed 8 mg/day 
Paroxetine  10 mg/day  4 mg/day  1.3   - Re-evaluate dosing. Do not exceed 8 mg/day
  20 mg/day  4 mg/day  1.6   -   
  40 mg/day  4 mg/day  1.8   -  
Enzyme (CYP3A/PgP inducers) Inducers          
Carbamazepine 573 ± 168 mg/day  3 mg twice daily  0.51 0.55  Titrate dose upwards. Do not exceed twice the patient’s usual dose 
Enzyme (CYP3A) Inhibitors          
Ranitidine  150 mg twice daily  1 mg single dose  1.2  1.4  Dose adjustment not needed 
Cimetidine  400 mg twice daily  1 mg single dose  1.1  1.3  Dose adjustment not needed 
Erythromycin  500 mg four times daily  1 mg single dose  1.1  0.94  Dose adjustment not needed 
Other Drugs           
Amitriptyline  50 mg twice daily  3 mg twice daily  1.2  1.1  Dose adjustment not needed 


Table name:
Table 25: Clinically Important Drug Interactions with Aripiprazole:
Concomitant Drug Name or Drug Class
Clinical Rationale
 
Clinical Recommendation
 

Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine)
The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].

With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].  

Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin) 
The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].

With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aipiprazole dosage
[see DOSAGE AND ADMINISTRATION (2.7)].

Antihypertensive Drugs  
Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.

Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.8)].

Benzodiazepines (e.g., lorazepam)
 
The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.8)]

Monitor sedation and blood pressure. Adjust dose accordingly.
 


Table name:
 
Drug Interactions Associated with Increased
Risk of Myopathy/Rhabdomyolysis (2.3 5.1, 7, 12.3)
 Interacting Agents  Prescribing Recommendations
 Strong CYP3A inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, and nefazodone), Erythromycin  Contraindicated with lovastatin
 Gemfibrozil, cyclosporine  Avoid with lovastatin
 Danazol, diltiazem, dronedarone, verapamil  Do not exceed 20 mg lovastatin daily
 Amiodarone  Do not exceed 40 mg lovastatin daily
 Grapefruit juice  Avoid grapefruit juice


Table name:
 Interacting Agents  Prescribing Recommendations
 Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)  Avoid atorvastatin
 HIV protease inhibitor (lopinavir plus ritonavir)  Use with caution and lowest dose necessary
 Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)  Do not exceed 20 mg atorvastatin daily
 HIV protease inhibitor (nelfinavir), Hepatitis C Protease inhibitor (boceprevir)  Do not exceed 40 mg atorvastatin daily


Table name:
Oral drugs that have to be separated from Phoslyra
 Dosing Recommendations
Flouroquinolones Take at least 2 hours before or 6 hours after Phoslyra
Tetracyclines Take at least 1 hour before Phoslyra
Levothyroxine Take at least 4 hours before or 4 hours after Phoslyra


Table name:
Table II. Clinically significant drug interactions with theophylline*.
DrugType of InteractionEffect**
*   Refer to PRECAUTIONS, Drug Interactions for further information regarding table.
** Average effect on steady state theophylline concentration or other clinical effect for pharmacologic interactions.
Individual patients may experience larger changes in serum theophylline concentration than the value listed
AdenosineTheophylline blocks adenosine receptors.Higher doses of adenosine may be required to achieve desired effect.
AlcoholA single large dose of alcohol (3 ml/kg of whiskey) decreases theophylline clearance for up to 24 hours.30% increase
AllopurinolDecreases theophylline clearance at allopurinol doses ≥600 mg/day.25% increase
AminoglutethimideIncreases theophylline clearance by induction of microsomal enzyme activity.25% decrease
CarbamazepineSimilar to aminoglutethimide30% decrease
CimetidineDecreases theophylline clearance by inhibiting cytochrome P450 1A2.70% increase
CiprofloxacinSimilar to cimetidine.40% increase
ClarithromycinSimilar to erythromycin.25% increase
DiazepamBenzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors.Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
DisulfiramDecreases theophylline clearance by inhibiting hydroxylation and demethylation.50% increase
EnoxacinSimilar to cimetidine.300% increase
EphedrineSynergistic CNS effectsIncreased frequency of nausea, nervousness, and insomnia.
ErythromycinErythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3.35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
EstrogenEstrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown.30% increase
FlurazepamSimilar to diazepam.Similar to diazepam.
FluvoxamineSimilar to cimetidineSimilar to cimetidine
HalothaneHalothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines.Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-ADecreases theophylline clearance.100% increase
Isoproterenol (IV)Increases theophylline clearance.20% decrease
KetaminePharmacologicMay lower theophylline seizure threshold.
LithiumTheophylline increases renal lithium clearance.Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
LorazepamSimilar to diazepam.Similar to diazepam.
Methotrexate (MTX)Decreases theophylline clearance.20% increase after low dose MTX, higher dose MTX may have a greater effect.
MexiletineSimilar to disulfiram.80% increase
MidazolamSimilar to diazepam.Similar to diazepam.
MoricizineIncreases theophylline clearance.25% decrease
PancuroniumTheophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition.Larger dose of pancuronium may be required to achieve neuromuscular blockade.
PentoxifyllineDecreases theophylline clearance.30% increase
Phenobarbital (PB)Similar to aminoglutethimide.25% decrease after two weeks of concurrent PB.
PhenytoinPhenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption.Serum theophylline and phenytoin concentrations decrease about 40%.
PropafenoneDecreases theophylline clearance and pharmacologic interaction.40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
PropranololSimilar to cimetidine and pharmacologic interaction.100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
RifampinIncreases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity.20-40% decrease
SulfinpyrazoneIncreases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline.20% decrease
TacrineSimilar to cimetidine, also increases renal clearance of theophylline.90% increase
ThiabendazoleDecreases theophylline clearance.190% increase
TiclopidineDecreases theophylline clearance.60% increase
TroleandomycinSimilar to erythromycin.33-100% increase depending on troleandomycin dose.
VerapamilSimilar to disulfiram.20% increase


Table name:
Interacting Drug
Interaction
Theophylline
Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin
Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents
Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin
Monitor phenytoin level (7)
Methotrexate
Monitor for methotrexate toxicity (7)
Cyclosporine
May increase serum creatinine. Monitor serum creatinine (7)
Multivalent cation-containing products including antacids, metal cations or didanosine
Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin (7)


Table name:
Interacting Drug Interaction
Theophylline Serious and fatal reactions. Avoid concomitant use. Monitor serum level ( 7)
Warfarin Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding ( 7)
Antidiabetic agents Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose ( 7)
Phenytoin Monitor phenytoin level ( 7)
Methotrexate Monitor for methotrexate toxicity ( 7)
Cyclosporine May increase serum creatinine. Monitor serum creatinine ( 7)
Multivalent cation-containing products including antacids, metal cations or didanosine Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin ( 7)


Table name:
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors          (e.g., itraconazole,    ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin,    HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Grapefruit juice Avoid grapefruit juice


Table name:
Table 6: Predicted Drug Interactions with Didanosine Delayed-Release Capsules
↑ Indicates increase.
Drug or Drug Class Effect Clinical Comment
Drugs that may cause pancreatic toxicity ↑risk of pancreatitis Use only with extreme caution.
Neurotoxic drugs ↑risk of neuropathy Use with caution.


Table name:
Increased Risk of Myopathy/Rhabdomyolysis (2, 5.1, 7, 12.3)
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
Lopinavir plus ritonavir Use lowest dose necessary
Clarithromycin, itraconazole,
HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)
Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Interacting Drug Interaction
Theophylline Serious and fatal reactions. Avoid concomitant use. Monitor serum level ( 7)
Warfarin Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding ( 7)
Antidiabetic agents Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose ( 7)
Phenytoin Monitor phenytoin level ( 7)
Methotrexate Monitor for methotrexate toxicity ( 7)
Cyclosporine May increase serum creatinine. Monitor serum creatinine ( 7)
Multivalent cation-containing products including antacids, metal cations or didanosine Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin ( 7)


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
↓ = Decreased (induces lamotrigine glucuronidation).
↑ = Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine Decreased lamotrigine concentrations approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? carbamazepine epoxide May increase carbamazepine epoxide levels.
Lopinavir/ritonavir ↓ lamotrigine Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir ↓ lamotrigine Decreased lamotrigine AUC approximately 32%.
Phenobarbital/Primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine

? valproate
Increased lamotrigine concentrations slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.


Table name:
Table 3 Established and Other Potentially SignificantThis table is not all inclusive. Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
Concomitant Drug Class: Drug Name Effect Clinical Comment
HIV antiviral agents
Protease inhibitor:
  atazanavir
↓atazanavir
↑ tenofovir
Coadministration of atazanavir with ATRIPLA is not recommended. Coadministration of atazanavir with either efavirenz or tenofovir DF decreases plasma concentrations of atazanavir. The combined effect of efavirenz plus tenofovir DF on atazanavir plasma concentrations is not known. Also, atazanavir has been shown to increase tenofovir concentrations. There are insufficient data to support dosing recommendations for atazanavir or atazanavir/ritonavir in combination with ATRIPLA.
Protease inhibitor:
  fosamprenavir calcium
↓ amprenavir Fosamprenavir (unboosted): Appropriate doses of fosamprenavir and ATRIPLA with respect to safety and efficacy have not been established.

Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when ATRIPLA is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when ATRIPLA is administered with fosamprenavir plus ritonavir twice daily.
Protease inhibitor:
  indinavir
↓ indinavir The optimal dose of indinavir, when given in combination with efavirenz, is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to efavirenz.
Protease inhibitor:
  lopinavir/ritonavir
↓ lopinavir
↑ tenofovir
Do not use once daily administration of lopinavir/ritonavir. Dose increase of lopinavir/ritonavir is recommended for all patients when coadministered with efavirenz. Refer to the full prescribing information for lopinavir/ritonavir for guidance on coadministration with efavirenz- or tenofovir-containing regimens, such as ATRIPLA. Patients should be monitored for tenofovir-associated adverse reactions.
Protease inhibitor:
  ritonavir
↑ ritonavir
↑ efavirenz
When ritonavir 500 mg every 12 hours was coadministered with efavirenz 600 mg once daily, the combination was associated with a higher frequency of adverse clinical experiences (e.g., dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when ATRIPLA is used in combination with ritonavir.
Protease inhibitor:
  saquinavir
↓ saquinavir Appropriate doses of the combination of efavirenz and saquinavir/ritonavir with respect to safety and efficacy have not been established.
CCR5 co-receptor antagonist:
  maraviroc
↓ maraviroc Efavirenz decreases plasma concentrations of maraviroc. Refer to the full prescribing information for maraviroc for guidance on coadministration with ATRIPLA.
NRTI:
  didanosine
↑ didanosine Coadministration of ATRIPLA and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse reactions including pancreatitis, lactic acidosis, and neuropathy. A dose reduction of didanosine is recommended when coadministered with tenofovir DF. For additional information on coadministration with tenofovir DF-containing products, please refer to the didanosine prescribing information.
NNRTI:
  Other NNRTIs
↑ or ↓ efavirenz and/or NNRTI Combining two NNRTIs has not been shown to be beneficial. ATRIPLA contains efavirenz and should not be coadministered with other NNRTIs.
Integrase strand transfer inhibitor:
  raltegravir
↓ raltegravir Efavirenz reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.
Hepatitis C antiviral agents
Protease inhibitor:
 boceprevir
↓ boceprevir Plasma trough concentrations of boceprevir were decreased when boceprevir was coadministered with efavirenz, which may result in loss of therapeutic effect. The combination should be avoided.
Protease inhibitor:
  simeprevir
↓ simeprevir
↔ efavirenz
Concomitant administration of simeprevir with efavirenz is not recommended because it may result in loss of therapeutic effect of simeprevir.
NS5A inhibitor/NS5B polymerase inhibitor :
  ledipasvir/sofosbuvir
↑ tenofovir Patients receiving ATRIPLA and HARVONI® (ledipasvir/sofosbuvir) concomitantly should be monitored for adverse reactions associated with tenofovir DF.
Other agents
Anticoagulant:
  warfarin
↑ or ↓ warfarin Plasma concentrations and effects potentially increased or decreased by efavirenz.
Anticonvulsants:
  carbamazepine
↓ carbamazepine
↓ efavirenz
There are insufficient data to make a dose recommendation for ATRIPLA. Alternative anticonvulsant treatment should be used.
  phenytoin
  phenobarbital
↓ anticonvulsant
↓ efavirenz
Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted.
Antidepressants:
  bupropion
↓ buproprion The effect of efavirenz on bupropion exposure is thought to be due to the induction of bupropion metabolism. Increases in bupropion dosage should be guided by clinical response, but the maximum recommended dose of bupropion should not be exceeded.
  sertraline ↓ sertraline Increases in sertraline dose should be guided by clinical response.
Antifungals:
  itraconazole
↓ itraconazole
↓ hydroxy-itraconazole
Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered.
  ketoconazole ↓ ketoconazole Drug interaction trials with ATRIPLA and ketoconazole have not been conducted. Efavirenz has the potential to decrease plasma concentrations of ketoconazole.
  posaconazole ↓ posaconazole Avoid concomitant use unless the benefit outweighs the risks.
Anti-infective:
  clarithromycin
↓ clarithromycin
↑ 14-OH metabolite
Clinical significance unknown. In uninfected volunteers, 46% developed rash while receiving efavirenz and clarithromycin. No dose adjustment of ATRIPLA is recommended when given with clarithromycin. Alternatives to clarithromycin, such as azithromycin, should be considered. Other macrolide antibiotics, such as erythromycin, have not been studied in combination with ATRIPLA.
Antimycobacterial:
  rifabutin
↓ rifabutin Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week.
  rifampin ↓ efavirenz If ATRIPLA is coadministered with rifampin to patients weighing 50 kg or more, an additional 200 mg/day of efavirenz is recommended.
Antimalarials:
  artemether/lumefantrine
↓ artemether
↓ dihydroartemisinin
↓ lumefantrine
Artemether/lumefantrine should be used cautiously with ATRIPLA because decreased artemether, dihydroartemisinin (active metabolite of artemether), and/or lumefantrine concentrations may result in a decrease of antimalarial efficacy of artemether/lumefantrine.
Calcium channel blockers:
  diltiazem
↓ diltiazem
↓ desacetyl diltiazem
↓ N-monodes-methyl diltiazem
Diltiazem dose adjustments should be guided by clinical response (refer to the full prescribing information for diltiazem). No dose adjustment of ATRIPLA is necessary when administered with diltiazem.
  Others (e.g.,
  felodipine, nicardipine,
  nifedipine, verapamil)
↓ calcium channel blocker No data are available on the potential interactions of efavirenz with other calcium channel blockers that are substrates of CYP3A. The potential exists for reduction in plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response (refer to the full prescribing information for the calcium channel blocker).
HMG-CoA reductase inhibitors:
  atorvastatin
  pravastatin
  simvastatin
↓ atorvastatin
↓ pravastatin
↓ simvastatin
Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased with efavirenz. Consult the full prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose.
Hormonal contraceptives:
Oral:
  ethinyl
  estradiol/norgestimate
↓ active metabolites of norgestimate A reliable method of barrier contraception must be used in addition to hormonal contraceptives. Efavirenz had no effect on ethinyl estradiol concentrations, but progestin levels (norelgestromin and levonorgestrel) were markedly decreased. No effect of ethinyl estradiol/norgestimate on efavirenz plasma concentrations was observed.
Implant:
  etonogestrel
↓ etonogestrel A reliable method of barrier contraception must be used in addition to hormonal contraceptives. The interaction between etonogestrel and efavirenz has not been studied. Decreased exposure of etonogestrel may be expected. There have been postmarketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients.
Immunosuppressants:
  cyclosporine,
  tacrolimus, sirolimus,
  and others
  metabolized by
  CYP3A
↓ immuno-suppressant Decreased exposure of the immunosuppressant may be expected due to CYP3A induction by efavirenz. These immunosuppressants are not anticipated to affect exposure of efavirenz. Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with ATRIPLA.
Narcotic analgesic:
  methadone
↓ methadone Coadministration of efavirenz in HIV-1 infected individuals with a history of injection drug use resulted in decreased plasma levels of methadone and signs of opiate withdrawal. Methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms. Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms.


Table name: Octreotide Tolbutamide Radiographic contrast agents) Sucralfate Tamoxifen Slow-Release Nicotinic Acid Salicylates (> 2 g/day) Rifampin Propylthiouracil (PTU) - Indandione Derivatives (SSRIs; e.g., Sertraline) - Insulin - Somatropin - (e.g., Theophylline) Thiazide Diuretics
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion – the reduction is not sustained;therefore, hypothyroidism does not occur
Dopamine / Dopamine Agonists Glucocorticoids
 
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( > 1 µg/kg/min); Glucocorticoids (hydrocortisone > 100 mg/day or equivalent); Octreotide ( > 100 µg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides
 
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T 4 and T 3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing
 
Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat
 
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane
 
Androgens / Anabolic Steroids Asparaginase Glucocorticoids
 
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone
 
Administration of these agents with levothyroxine results in an initial transient increase in FT 4. Continued administration results in a decrease in serum T 4 and normal FT 4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T 4 and T 3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT 4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T 4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital
 
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T 4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5’-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone > 4 mg/day)
 
Administration of these enzyme inhibitors decreases the peripheral conversion of T 4 to T 3, leading to decreased T 3 levels. However, serum T 4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T 3 and T 4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T 3 concentrations by 30% with minimal change in serum T 4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T 3 and T 4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives
 
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors
 
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones
 
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Growth Hormones - Somatrem
 
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
 
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use)
 
These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.


Table name:
Table 7: Summary of AED Interactions with Oxcarbazepine
AED Coadministered Dose of AED (mg/day) Oxcarbazepine Dose (mg/day) Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval) Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine
400 to 2,000
900
nc nc denotes a mean change of less than 10%
40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital
100 to 150
600 to 1,800
14% increase [CI: 2% increase, 24% increase]
25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin
250 to 500
600 to 1,800 >1,200 to 2,400
nc Pediatrics
up to 40% increase Mean increase in adults at high oxcarbazepine doses [CI: 12% increase, 60% increase]
30% decrease [CI: 3% decrease, 48% decrease]
Valproic acid
400 to 2,800
600 to 1,800
nc
18% decrease [CI: 13% decrease, 40% decrease]


Table name:
Interacting Drug Interaction
Theophylline Serious and fatal reactions. Avoid concomitant use. Monitor serum level ( 7)
Warfarin Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding ( 7)
Antidiabetic agents Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose ( 7)
Phenytoin Monitor phenytoin level ( 7)
Methotrexate Monitor for methotrexate toxicity ( 7)
Cyclosporine May increase serum creatinine. Monitor serum creatinine ( 7)
Multivalent cation-containing products including antacids, metal cations or didanosine Decreased ciprofloxacin tablets absorption. Take 2 hours before or 6 hours after ciprofloxacin tablets ( 7)


Table name:
Table 14: Clinically Important Drug Interactions: Effect of Other Drugs on Guanfacine Extended-Release Tablets
Concomitant Drug Name or Drug Class Clinical Rationale and Magnitude of Drug Interaction Clinical Recommendation
Strong and moderate
CYP3A4 inhibitors, e.g., ketoconazole, fluconazole
Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected resulting in an increase in exposure Consider dose reduction [see Dosage and Administration (2.7) ]
Strong and moderate
CYP3A4 inducers, e.g., rifampin, efavirenz
Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected resulting in a decrease in exposure Consider dose increase [see Dosage and Administration (2.7) ]


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
  Factors   Dosage Adjustment of aripiprazole
 Known CYP2D6 Poor Metabolizers  Administer half of usual dose
 Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors  Administer a quarter of usual dose
 Strong CYP2D6 CYP3A4 inhibitors or  Administer half of usual dose
 Strong CYP2D6 CYP3A4 inhibitors and  Administer a quarter of usual dose
 Strong CYP3A4 inducers  Double usual dose over 1 to 2 weeks


Table name:
Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.*
 *    Refer to PRECAUTIONS, Drug Interactions for information regarding table.
 albuterol, systemic and inhaled  hydrocortisone  ofloxacin
 amoxicillin  isoflurane  omeprazole
 ampicillin, with or without  isoniazid  prednisone, prednisolone
   sulbactam  isradipine  ranitidine
 atenolol  influenza vaccine  rifabutin
 azithromycin  ketoconazole  roxithromycin
 caffeine, dietary ingestion  lomefloxacin  sorbitol
 cefaclor  mebendazole    (purgative doses do
 co-trimoxazole (trimethoprim  medroxyprogesterone    not inhibit theophylline
    and sulfamethoxazole)  methylprednisolone    absorption)
 diltiazem  metronidazole  sucralfate
 dirithromycin  metoprolol  terbutaline,systemic
 enflurane  nadolol  terfenadine
 famotidine  nifedipine  tetracycline
 felodipine  nizatidine  tocainide
 finasteride  norfloxacin  


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg. ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine

↓levonorgestrel
Decreased lamotrigine concentrations approximately 50%.
Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide ↓ lamotrigine

? carbamazepine epoxide
Addition of carbamazepine decreases lamotrigine concentration approximately 40%.  
May increase carbamazepine epoxide levels.
Lopinavir/ritonavir ↓ lamotrigine Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir ↓ lamotrigine Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine


? valproate
Increased lamotrigine concentrations slightly more than 2-fold.

There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.


Table name:
Concomitant Drug Name or Drug Class Clinical Rationale Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)]. With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin) The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)]. With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Antihypertensive Drugs Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.8)].
Benzodiazepines (e.g., lorazepam) The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.8)] Monitor sedation and blood pressure. Adjust dose accordingly.


Table name:
Interacting Drug Interaction
Theophylline Serious and fatal reactions. Avoid concomitant use. Monitor serum level ( 7)
Warfarin Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding ( 7)
Antidiabetic agents Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose ( 7)
Phenytoin Monitor phenytoin level ( 7)
Methotrexate Monitor for methotrexate toxicity ( 7)
Cyclosporine May increase serum creatinine. Monitor serum creatinine ( 7)
Multivalent cation-containing products including antacids, metal cations, or didanosine Decreased Ciprofloxacin absorption. Take 2 hours before or 6 hours after Ciprofloxacin ( 7)


Table name:
Table 7:  Summary of AED Interactions with Oxcarbazepine
1nc denotes a mean change of less than 10%
2Pediatrics
3Mean increase in adults at high oxcarbazepine doses
AED
Coadministered
Dose of AED
(mg/day)
Oxcarbazepine Dose
(mg/day)
Influence of
Oxcarbazepine on AED
Concentration
(Mean Change,
90% Confidence
Interval)
Influence of
AED on MHD
Concentration
(Mean Change,
90% Confidence
Interval)
Carbamazepine
400 to 2000
900
nc 1
40% decrease
[CI: 17% decrease,
57% decrease]
Phenobarbital
100 to150
600 to 1800
14% increase
[CI: 2% increase,
24% increase]
25% decrease
[CI: 12% decrease,
51% decrease]
Phenytoin
250 to 500
600 to 1800
>1200 to 2400
nc 1,2
up to 40%
increase 3
[CI: 12% increase,
60% increase]
30% decrease
[CI: 3% decrease,
48% decrease]
Valproic acid
400 to 2800
600 to 1800
nc 1
18% decrease
[CI: 13% decrease,
40% decrease]
Lamotrigine
200
1200
nc 1
nc 1


Table name:
Antibiotics Antineoplastics Anti-inflammatory Drugs Gastrointestinal Agents
ciprofloxacin melphalan azapropazon cimetidine
gentamicin   colchicine ranitidine
tobramycin Antifungals diclofenac  
vancomycin amphotericin B naproxen Immunosuppressives
trimethoprim with sulfamethoxazole ketoconazole sulindac tacrolimus
       
      Other Drugs
      fibric acid derivatives
      (e.g.,bezafibrate, fenofibrate)
methotrexate


Table name:
Drugs That Interfere with Hemostasis
Clinical Impact: Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of diclofenac sodium topical gel with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ see Warnings and Precautions (5.2)].
Intervention: Concomitant use of diclofenac sodium topical gel and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions (5.11)]. Diclofenac sodium topical gel is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol) In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: During concomitant use of diclofenac sodium topical gel and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of diclofenac sodium topical gel and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of diclofenac sodium topical gel with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ see Warnings and Precautions (5.6)].
Digoxin
Clinical Impact: The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of diclofenac sodium topical gel and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of diclofenac sodium topical gel and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of diclofenac sodium topical gel and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of diclofenac sodium topical gel and cyclosporine may increase cyclosporine's nephrotoxicity.
Intervention: During concomitant use of diclofenac sodium topical gel and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ see Warnings and Precautions (5.2)].
Intervention: The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of diclofenac sodium topical gel and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of diclofenac sodium topical gel and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and Gl toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.


Table name:
Table 3 Clinically Significant Drug Interactions with Meloxicam
Drugs  that  Interfere  with  Hemostasis
Clinical  Impact :
Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.
Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. 
Intervention
Monitor patients with concomitant use of meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see  Warnings  and  Precautions  ( 5 . 11)]. 
Aspirin 
Clinical  Impact
Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see  Warnings  and  Precautions  ( 5 . 2)]. 
Intervention
Concomitant use of meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see  Warnings  and  Precautions  ( 5 . 11)]. 

Meloxicam is not a substitute for low dose aspirin for cardiovascular protection. 
ACE  Inhibitors Angiotensin  Receptor  Blockers or  Beta - Blockers 
Clinical  Impact

NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). 
In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. 
Intervention

During concomitant use of meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. 
During concomitant use of meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see  Warnings  and  Precautions  ( 5 . 6)]. 
When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. 
Diuretics 

Clinical  Impact

Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. 
Intervention

During concomitant use of meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see  Warnings  and  Precautions  ( 5 . 6)]. 
Lithium 
Clinical  Impact

NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [see  Clinical  Pharmacology  ( 12 . 3)]. 
Intervention

During concomitant use of meloxicam and lithium, monitor patients for signs of lithium toxicity. 
Methotrexate 
Clinical  Impact

Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention

During concomitant use of meloxicam and methotrexate, monitor patients for methotrexate toxicity. 
Cyclosporine 

Clinical  Impact

Concomitant use of meloxicam and cyclosporine may increase cyclosporine’s nephrotoxicity. 
Intervention

During concomitant use of meloxicam and cyclosporine, monitor patients for signs of worsening renal function. 
NSAIDs  and  Salicylates 

Clinical  Impact

Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see  Warnings  and  Precautions  ( 5 . 2)]. 
Intervention

The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended. 
Pemetrexed 

Clinical  Impact

Concomitant use of meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). 
Intervention

During concomitant use of meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended. 


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
 Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration  Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
 Drugs that may alter T 4 and T 3 metabolism
 Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Drugs   That   Interfere  with   Hemostasis
Clinical   Impact: 
·    Naproxen   and   anticoagulants   such  as   warfarin   have  a   synergistic   effect   on   bleeding.  The   concomitant  use  of naproxen  and anticoagulants have   an   increased risk  of serious   bleeding  compared   to   the  use  of   either  drug   alone.
·    Serotonin   release by  platelets   plays an important  role in   hemostasis.  Case-control and  cohort   epidemiological  studies   showed  that   concomitant  use  of  drugs   that   interfere   with   serotonin   reuptake  and  an   NSAID  may   potentiate  the  risk   of bleeding   more  than  an   NSAID   alone. 
Intervention: 
Monitor   patients   with   concomitant  use  of  naproxen sodium  with   anticoagulants   (e.g.,   warfarin),   antiplatelet  agents   (e.g.,   aspirin),   selective  serotonin   reuptake   inhibitors  (SSRIs),   and   serotonin   norepinephrine   reuptake   inhibitors   (SNRIs)   for   signs   of   bleeding  [see  Warnings  and  Precautions   (5.11) ].
Aspirin 
Clinical   Impact: 
Controlled   clinical   studies   showed  that  the   concomitant  use  of  NSAIDs   and   analgesic  doses  of aspirin does not  produce   any greater therapeutic effect   than the  use   of  NSAIDs   alone.  In  a   clinical   study,  the   concomitant  use  of  an  NSAID   and   aspirin   was   associated   with  a   significantly   increased   incidence  of  GI  adverse   reactions   as  compared   to  use  of   the   NSAID  alone   [see  Warnings and Precautions ( 5.2 ) ].
Intervention: 
Concomitant use of naproxen sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see   Warnings and Precautions (5.11) ].
Naproxen sodium is not substitutes for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers 
Clinical   Impact: 
·    NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).
·    In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment,co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. 
Intervention: 
·    During concomitant use of naproxen sodium and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.
·    During concomitant use of naproxen sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see  Warnings and Precautions ( 5.6 ) ].
·    When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. 
Diuretics 
Clinical   Impact: 
Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: 
During concomitant use of naproxen sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see   Warnings and Precautions ( 5.6 ) ].
Digoxin 
Clinical   Impact: 
The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin
Intervention: 
During concomitant use of naproxen sodium and digoxin, monitor serum digoxin levels.
Lithium 
Clinical   Impact: 
NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance.  The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: 
During concomitant use of naproxen sodium and lithium, monitor patients for signs of lithium toxicity.
Methotrexate 
Clinical   Impact: 
Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: 
During concomitant use of naproxen sodium and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine 
Clinical   Impact: 
Concomitant use of naproxen sodium and cyclosporine may increase cyclosporine’s nephrotoxicity. 
Intervention: 
During concomitant use of naproxen sodium and cyclosporine, monitor patients for signs of worsening renal function. 
NSAIDs and Salicylates 
Clinical   Impact: 
Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see  Warnings and Precautions ( 5.2 ) ].
Intervention: 
The concomitant   use   of   naproxen   with   other   NSAIDs   or   salicylates   is   not recommended.
Pemetrexed 
Clinical   Impact: 
Concomitant use of naproxen sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: 
During concomitant use of naproxen sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.
 
NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.
 
In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids   and Sucralfate 
Clinical   Impact: 
Concomitant administration of  some  antacids (magnesium  oxide  or  aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention: 
Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen sodium is not recommended.
Cholestyramine 
Clinical   Impact: 
Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention: 
Concomitant administration   of  cholestyramine   with naproxen sodium is not recommended.
Probenecid 
Clinical   Impact: 
Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention: 
Patients simultaneously   receiving   naproxen sodium and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs 
Clinical   Impact: 
Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention: 
Patients simultaneously receiving naproxen sodium and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.


Table name:
Table 3: Clinically Significant drug interactions with Celecoxib
Drugs That Interfere with Hemostasis
Clinical Impact:
Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of Celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.
Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:
Monitor patients with concomitant use of celecoxib capsules with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact:
Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions ( 5.2 )]. In two studies in healthy volunteers, and in patients with osteoarthritis and established heart disease respectively, celecoxib (200-400 mg daily) has demonstrated a lack of interference with the cardioprotective antiplatelet effect of aspirin (100-325 mg).
Intervention:
Concomitant use of celecoxib capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. Celecoxib capsules are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:
NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).
In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:
During concomitant use of celecoxib capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of celecoxib capsules and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:
Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:
During concomitant use of celecoxib capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Digoxin
Clinical Impact:
The concomitant use of Celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:
During concomitant use of celecoxib capsules and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:
NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:
During concomitant use of celecoxib capsules and lithium, monitor patients for signs of lithium toxicity. 
Methotrexate 
Clinical Impact:
Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). 

Celecoxib has no effect on methotrexate pharmacokinetics. 
Intervention:
During concomitant use of celecoxib capsules and methotrexate, monitor patients for methotrexate toxicity. 
Cyclosporine 
Clinical Impact:
Concomitant use of celecoxib capsules and cyclosporine may increase cyclosporine’s nephrotoxicity. 
Intervention:
During concomitant use of celecoxib capsules and cyclosporine, monitor patients for signs of worsening renal function. 
NSAIDs and Salicylates 
Clinical Impact:
Concomitant use of Celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention:
The concomitant use of Celecoxib with other NSAIDs or salicylates is not recommended. 
Pemetrexed 
Clinical Impact:
Concomitant use of celecoxib capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). 
Intervention:
During concomitant use of celecoxib capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. 

NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. 

In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. 
CYP2C9 Inhibitors or inducers 
Clinical Impact:
Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Coadministration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of celecoxib. 
Intervention:
Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers. [see Clinical Pharmacology (12.3)].
CYP2D6 substrates 
Clinical Impact:
In vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6 (e.g. atomoxetine), and celecoxib may enhance the exposure and toxicity of these drugs. 
Intervention:
Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2D6 substrates. [see Clinical Pharmacology (12.3)].
Corticosteroids 
Clinical Impact:
Concomitant use of corticosteroids with celecoxib capsules may increase the risk of GI ulceration or bleeding. 
Intervention:
Monitor patients with concomitant use of celecoxib capsules with corticosteroids for signs of bleeding [see Warnings and Precautions (5.2)].


Table name:
Antibiotics Anticonvulsants Other Drugs/DietarySupplements
nafcillin carbamazepine bosentan  St. John’s Wort
rifampin oxcarbazepine octreotide
phenobarbital orlistat
phenytoin sulfinpyrazone
terbinafine
ticlopidine


Table name:
Antibiotics Anticonvulsants Other Drugs/Dietary Supplements
nafcillin carbamazepine bosentan
rifampin oxcarbazepine octreotide
  phenobarbital orlistat
  phenytoin sulfinpyrazone
    St. John's Wort
    terbinafine
    ticlopidine


Table name:

a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
b = Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated
AED Co-administered 
AED Concentration
Topiramate Concentration
Phenytoin 
NC or 25% increasea
48% decrease
Carbamazepine (CBZ)
NC 
40% decrease
CBZ epoxideb
NC
NE
Valproic acid 
11% decrease
14% decrease
Phenobarbital
NC
NE
Primidone 
NC
NE
Lamotrigine 
NC at TPM doses up to 400 mg/day
13% decrease


Table name:
Drugs that Affect Renal Function A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDS], COX-2 inhibitors may impair the excretion of digoxin.
Antiarrthymics Dofetilide Concomitant administration with digoxin was associated with a higher rate of torsades de pointes
Sotalol Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
Dronedarone Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone Analog Teriparatide Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement Thyroid Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics Epinephrine
Norepinephrine     
Dopamine
Can increase the risk of cardiac arrhythmias
Neuromuscular Blocking Agents      Succinylcholine May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.
Supplements Calcium If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.
Hyperpolarization-activated cyclic nucleotide-gated channel blocker Ivabradine Can increase the risk of bradycardia


Table name:
Table 9: Clinically Important Drug Interactions with VRAYLAR
Strong CYP3A4 Inhibitors
Clinical Impact: Concomitant use of VRAYLAR with a strong CYP3A4 inhibitor increases the exposures of cariprazine and its major active metabolite, didesmethylcariprazine (DDCAR), compared to use of VRAYLAR alone [see Clinical Pharmacology (12.3)].
Intervention: If VRAYLAR is used with a strong CYP3A4 inhibitor, reduce VRAYLAR dosage [see Dosage and Administration (2.3)].
Examples: itraconazole, ketoconazole
CYP3A4 Inducers
Clinical Impact: CYP3A4 is responsible for the formation and elimination of the active metabolites of cariprazine. The effect of CYP3A4 inducers on the exposure of VRAYLAR has not been evaluated, and the net effect is unclear [see Clinical Pharmacology (12.3)].
Intervention: Concomitant use of VRAYLAR with a CYP3A4 inducer is not recommended [see Dosage and Administration (2.1, 2.3)].
Examples: rifampin, carbamazepine


Table name: Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.During concomitant use of diclofenac sodium delayed-release tablets and ACE-inhibitors, ARBs, or beta- blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of diclofenac sodium delayed-release tablets and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS: Renal Toxicity and Hyperkalemia ). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Table 2. Clinically Significant Drug Interactions with Diclofenac
Drugs That Interfere with Hemostasis
Clinical Impact:
Intervention: Monitor patients with concomitant use of diclofenac sodium delayed-release tablets with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS: Hematologic Toxicity ).
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation ).
Intervention: Concomitant use of diclofenac sodium delayed-release tablets and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS: Hematologic Toxicity ). Diclofenac sodium delayed-release tablets are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:
Intervention:
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of diclofenac sodium delayed-release tablets with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS: Renal Toxicity and Hyperkalemia ).
Digoxin
Clinical Impact: The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of diclofenac sodium delayed-release tablets and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of diclofenac sodium delayed-release tablets and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of diclofenac sodium delayed-release tablets and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of diclofenac sodium delayed-release tablets and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of diclofenac sodium delayed-release tablets and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation ).
Intervention: The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of diclofenac sodium delayed-release tablets and pemetrexed may increase the risk of pemetrexed‑ associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of diclofenac sodium delayed-release tablets and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
CYP2C9 Inhibitors or Inducers:
Clinical Impact: Diclofenac is metabolized by cytochrome P450 enzymes, predominantly by CYP2C9. Co-administration of diclofenac with CYP2C9 inhibitors (e.g. voriconazole) may enhance the exposure and toxicity of diclofenac whereas co‑administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of diclofenac.
Intervention: A dosage adjustment may be warranted when diclofenac is administered with CYP2C9 inhibitors or inducers (see CLINICAL PHARMACOLOGY: Pharmacokinetics ).


Table name:
Factors Dosage Adjustment of Aripiprazole tablets
Known CYP2D6 Poor Metabolizers Administer half of usual dose
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors Administer half of usual dose
Strong CYP2D6 andCYP3A4 inhibitors Administer a quarter of usual dose
Strong CYP3A4 inducers Double usual dose over 1 to 2 weeks


Table name:
  Digoxin concentrations increased greater than 50%
          Digoxin Serum     
Concentration
Increase
       Digoxin AUC     
Increase
  Recommendations
  Quinidine   NA    54-83%  Measure serum digoxin concentrations before     
initiating concomitant drugs. Reduce digoxin
concentrations by decreasing dose by
approximately 30-50% or by modifying the
dosing frequency and continue monitoring.
  Ritonavir   NA   86%
  Digoxin concentrations increased less than 50%
  Amiodarone   17%   40%  Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring.
  Propafenone   28%   29%
  Quinine   NA   34-38%
  Spironolactone        NA   44%
  Verapamil   NA   24%


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.10, 7.3)


Table name:
Antibiotics Antineoplastic   Antifungals           Anti-
Inflammatory
Drugs
Gastrointestinal 
Agents
Immunosuppressives     Other Drugs
ciprofloxacingentamicin tobramycin trimethoprim with sulfamethoxazole vancomycin melphalan amphotericin Bketoconazole azapropazoncolchicine diclofenacnaproxen sulindac cimetidine ranitidine tacrolimus fibric acid
derivatives (e.g., bezafibrate, 
fenofibrate) methotrexate


Table name:
Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s) Recommendation Comments
Tizanidine Contraindicated Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)].
Theophylline Avoid Use (Plasma Exposure Likely to be Increased and Prolonged) Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate[see Warnings and Precautions (5.6).]
Drugs Known to Prolong QT Interval Avoid Use Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.10) and Use in Specific Populations (8.5)].
Oral antidiabetic drugs Use with caution Glucose-lowering effect potentiated Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs. [see Adverse Reactions (6.1).]
Phenytoin Use with caution Altered serum levels of phenytoin (increased and decreased) To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after coadministration of ciprofloxacin with phenytoin.
Cyclosporine Use with caution (transient elevations in serum creatinine) Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs Use with caution (Increase in anticoagulant effect) The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole Use with caution Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after coadministration with ciprofloxacin [see Warnings and Precautions (5.15)].
Clozapine Use with caution Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs Use with caution Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil Use with caution 2-fold increase in exposure Monitor for sildenafil toxicity (see Pharmacokinetics -(12.3)-].
Duloxetine Avoid Use 5-fold increase in duloxetine exposure If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products) Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2)]. Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels) Potentiation of ciprofloxacin toxicity may occur.


Table name:
Table 18. Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug Dosing Schedule Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio Change relative to reference ) Risperidone Dose Recommendation
Coadministered Drug Risperidone AUC Cmax
Enzyme (CYP2D6) Inhibitors
Fluoxetine 20 mg/day 2 mg or
3 mg twice daily
1.4 1.5 Reevaluate dosing. Do not exceed 8 mg/day
Paroxetine 10 mg/day 4 mg/day 1.3 -- Reevaluate dosing. Do not exceed 8 mg/day
20 mg/day 4 mg/day 1.6 --
40 mg/day - 4 mg/day 1.8 --
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine 573 ± 168 mg/day 3 mg twice daily 0.51 0.55 Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine 150 mg twice daily 1 mg single dose 1.2 1.4 Dose adjustment not needed
Cimetidine 400 mg twice daily 1 mg single dose 1.1 1.3 Dose adjustment not needed
Erythromycin 500 mg four times daily 1 mg single dose 1.1 0.94 Dose adjustment not needed
Other Drugs
Amitriptyline 50 mg twice daily 3 mg twice daily 1.2 1.1 Dose adjustment not needed


Table name:
Table 8: Clinically Significant Drug Interactions with Clarithromycin
Drugs That Are Affected By Clarithromycin
Drug(s) with Pharmacokinetics Affected by Clarithromycin
Recommendation
Comments
Antiarrhythmics:
 
Disopyramide
Quinidine
Dofetilide
Amiodarone
Sotalol
Procainamide
 
 
 
 
Digoxin
 
 
Not Recommended
 
 
 
 
 
 
 
 
Use With Caution
 
 
Disopyramide, Quinidine: There have been postmarketing reports of torsades de pointes occurring with concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QTc prolongation during coadministration of clarithromycin with these drugs [see Warnings and Precautions (5.3)] .
 
Serum concentrations of these medications should also be monitored. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with disopyramide and quinidine.
 
There have been postmarketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide. Therefore, blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide.
 
Digoxin: Digoxin is a substrate for P-glycoprotein (Pgp) and clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are co-administered, inhibition of Pgp by clarithromycin may lead to increased exposure of digoxin. Elevated digoxin serum concentrations in patients receiving clarithromycin and digoxin concomitantly have been reported in postmarketing surveillance. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Monitoring of serum digoxin concentrations should be considered, especially for patients with digoxin concentrations in the upper therapeutic range.
Oral Anticoagulants:
 
Warfarin
 
 
Use With Caution
 
 
Oral anticoagulants: Spontaneous reports in the postmarketing period suggest that concomitant administration of clarithromycin and oral anticoagulants may potentiate the effects of the oral anticoagulants. Prothrombin times should be carefully monitored while patients are receiving clarithromycin and oral anticoagulants simultaneously [see Warnings and Precautions (5.4)] .
Antiepileptics:
 
Carbamazepine
 
 
Use With Caution
 
 
Carbamazepine: Concomitant administration of single doses of clarithromycin and carbamazepine has been shown to result in increased plasma concentrations of carbamazepine. Blood level monitoring of carbamazepine may be considered. Increased serum concentrations of carbamazepine were observed in clinical trials with clarithromycin. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with carbamazepine.
Antifungals:
 
Itraconazole
 
 
 

Fluconazole
 
 
Use With Caution
 
 
 

No Dose Adjustment
 
 
Itraconazole: Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when administered concomitantly (see also Itraconazole under “Drugs That Affect Clarithromycin” in the table below). Clarithromycin may increase the plasma concentrations of itraconazole. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions.
 
Fluconazole:  [see Pharmacokinetics (12.3)]
 

Anti-Gout Agents:
 
Colchicine (in patients with renal or hepatic impairment)
 
Colchicine (in patients with normal renal and hepatic function)
 
 
Contraindicated
 
 
Use With Caution
 
 
Colchicine: Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. The dose of colchicine should be reduced when co-administered with clarithromycin in patients with normal renal and hepatic function [see  Contraindications (4.4) and Warnings and Precautions (5.4)] .
Antipsychotics:
 
Pimozide
 
Quetiapine
 
 
Contraindicated
 
 
Pimozide:  [See Contraindications (4.2)]

Quetiapine: Quetiapine is a substrate for CYP3A4, which is inhibited by clarithromycin. Co-administration with clarithromycin could result in increased quetiapine exposure and possible quetiapine related toxicities. There have been postmarketing reports of somnolence, orthostatic hypotension, altered state of consciousness, neuroleptic malignant syndrome, and QT prolongation during concomitant administration. Refer to quetiapine prescribing information for recommendations on dose reduction if co-administered with CYP3A4 inhibitors such as clarithromycin.
Antispasmodics:
 
Tolterodine (patients deficient in CYP2D6 activity)
 
 
Use With Caution
 
 
Tolterodine: The primary route of metabolism for tolterodine is via. CYP2D6. However, in a subset of the population devoid of CYP2D6, the identified pathway of metabolism is via. CYP3A. In this population subset, inhibition of CYP3A results in significantly higher serum concentrations of tolterodine. Tolterodine 1 mg twice daily is recommended in patients deficient in CYP2D6 activity (poor metabolizers) when co-administered with clarithromycin.
Antivirals:
 
Atazanavir
 

Saquinavir (in patients with decreased renal function)
 
Ritonavir
Etravirine
 
Maraviroc
 

Boceprevir (in patients with normal renal function)
 
Didanosine
 
Zidovudine


 
 
Use With Caution
 
 
 
 
 
 
 
 
 
 

No Dose Adjustment
 
 
Atazanavir: Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction (see Atazanavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)] .
 
Saquinavir: Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A and there is evidence of a bi-directional drug interaction (see Saquinavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)] .
 
Ritonavir, Etravirine: (see Ritonavir and Etravirine under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)] .
 

Maraviroc
: Clarithromycin may result in increases in maraviroc exposures by inhibition of CYP3A metabolism. See Selzentry ® prescribing information for dose recommendation when given with strong CYP3A inhibitors such as clarithromycin.
 
Boceprevir: Both clarithromycin and boceprevir are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when co-administered. No dose adjustments are necessary for patients with normal renal function (see Victrelis ® prescribing information).
 


Zidovudine:
Simultaneous oral administration of clarithromycin immediate-release tablets and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine concentrations. Administration of clarithromycin and zidovudine should be separated by at least two hours [see Pharmacokinetics (12.3)] .
Calcium Channel Blockers:
 
Verapamil
 

Amlodipine
Diltiazem
 
Nifedipine
 
 
Use With Caution
 
 
Verapamil: Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent verapamil, [see Warnings and Precautions (5.4)] .
 
Amlodipine, Diltiazem: [See Warnings and Precautions (5.4)]

 
Nifedipine: Nifedipine is a substrate for CYP3A. Clarithromycin and other macrolides are known to inhibit CYP3A. There is potential of CYP3A-mediated interaction between nifedipine and clarithromycin. Hypotension and peripheral edema were observed when clarithromycin was taken concomitantly with nifedipine [see Warnings and Precautions (5.4)] .
Ergot Alkaloids:
 
Ergotamine
Dihydroergotamine
 
 
Contraindicated
 
 
Ergotamine, Dihydroergotamine: Postmarketing reports indicate that coadministration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system [see Contraindications (4.6)].
Gastroprokinetic  Agents:
 
Cisapride
 
 
Contraindicated
 
 
Cisapride: [See Contraindications (4.2)]
HMG-CoA Reductase Inhibitors:
 
Lovastatin
Simvastatin
 
Atorvastatin
Pravastatin
 
Fluvastatin

 
 
Contraindicated
 
 
Use With Caution
 
No Dose Adjustment
 
 
Lovastatin, Simvastatin, Atorvastatin, Pravastatin, Fluvastatin:  [See  Contraindications (4.5) and Warnings and Precautions (5.4)]
Hypoglycemic Agents:
 
Nateglinide
Pioglitazone
Repaglinide
Rosiglitazone
 
Insulin

 
 
Use With Caution
 
 
Nateglinide, Pioglitazone, Repaglinide, Rosiglitazone: [See Warnings and Precautions (5.4) and Adverse Reactions (6.2)]
 



Insulin: [See  Warnings and Precautions (5.4) and Adverse Reactions (6.2)]
Immunosuppressants:
 
Cyclosporine
 
Tacrolimus
 
 
Use With Caution
 
 
Cyclosporine: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with cyclosporine.
 
Tacrolimus: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with tacrolimus.
Phosphodiesterase inhibitors:
 
Sildenafil
Tadalafil
Vardenafil
 
 
 
Use With Caution
 
 
 
Sildenafil, Tadalafil, Vardenafil: Each of these phosphodiesterase inhibitors is primarily metabolized by CYP3A, and CYP3A will be inhibited by concomitant administration of clarithromycin. Co-administration of clarithromycin with sildenafil, tadalafil, or vardenafil will result in increased exposure of these phosphodiesterase inhibitors. Co-administration of these phosphodiesterase inhibitors with clarithromycin is not recommended. Increased systemic exposure of these drugs may occur with clarithromycin; reduction of dosage for phosphodiesterase inhibitors should be considered (see their respective prescribing information).
Proton Pump Inhibitors:
 
Omeprazole
 
 
No Dose Adjustment
 
 
Omeprazole: The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when coadministered with clarithromycin as a result of increased omeprazole exposures [see Pharmacokinetics (12.3)] (see also Omeprazole under “Drugs That Affect Clarithromycin” in the table below).
Xanthine Derivatives:
 
Theophylline
 
 
Use With Caution
 
 
Theophylline: Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serum theophylline concentrations [see Pharmacokinetics (12.3)] . Monitoring of serum theophylline concentrations should be considered for patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range.
Triazolobenzodiazepines and Other Related Benzodiazepines:
 
Midazolam
 
 
Alprazolam
Triazolam
 
 
 
 
 
Temazepam
Nitrazepam
Lorazepam
 
 
 
Use With Caution
 
 
 
 
 
 
 
 
 
No Dose Adjustment
 
 
 
Midazolam: When oral midazolam is co-administered with clarithromycin, dose adjustments may be necessary and possible prolongation and intensity of effect should be anticipated [see  Warnings and Precautions (5.4) and Pharmacokinetics (12.3)] .
 
Triazolam, Alprazolam: Caution and appropriate dose adjustments should be considered when triazolam or alprazolam is co-administered with clarithromycin. There have been postmarketing reports of drug interactions and central nervous system (CNS) effects (e.g., somnolence and confusion) with the concomitant use of clarithromycin and triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested.
 
In postmarketing experience, erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines.
 
Temazepam, Nitrazepam, Lorazepam: For benzodiazepines which are not metabolized by CYP3A (e.g., temazepam, nitrazepam, lorazepam), a clinically important interaction with clarithromycin is unlikely.
Cytochrome P450 Inducers:
 
Rifabutin
 
 
Use With Caution
 
 
Rifabutin: Concomitant administration of rifabutin and clarithromycin resulted in an increase in rifabutin, and decrease in clarithromycin serum levels together with an increased risk of uveitis (see Rifabutin under “Drugs That Affect Clarithromycin” in the table below).
Other Drugs
Metabolized by CYP3A:
 
Alfentanil
Bromocriptine
Cilostazol
Methylprednisole Vinblastine
Phenobarbital
St. John’s Wort
 
 
 
Use With Caution
 
 
 
There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with alfentanil, methylprednisolone, cilostazol, bromocriptine, vinblastine, phenobarbital, and St. John’s Wort.
Other Drugs Metabolized by CYP450 Isoforms Other than CYP3A:
 
Hexobarbital
Phenytoin
Valproate
 
 
 
 
Use With Caution
 
 
 
 
There have been postmarketing reports of interactions of clarithromycin with drugs not thought to be metabolized by CYP3A, including hexobarbital, phenytoin, and valproate.


                                                                                                                                       Drugs that Affect Clarithromycin
Drug(s) that Affect the Pharmacokinetics of Clarithromycin

Recommendation

                                                                                     Comments
Antifungals:
 
Itraconazole
 
 
Use With Caution
 
 
Itraconazole: Itraconazole may increase the plasma concentrations of clarithromycin. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions (see also Itraconazole under “Drugs That Are Affected By Clarithromycin” in the table above).
Antivirals:
 
Atazanavir
 
 
 
 
 
 
Ritonavir (in patients with decreased renal function)
 
 
Saquinavir (in patients with decreased renal function)
 
Etravirine
 
 
 
 
Saquinavir (in patients with normal renal function) Ritonavir (in patients with normal renal function)
 
 
Use With Caution
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
No Dose Adjustment
 
 
Atazanavir: When clarithromycin is co-administered with atazanavir, the dose of clarithromycin should be decreased by 50% [see Clinical Pharmacology (12.3)] .
 
Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with atazanavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium complex. Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.
 
Ritonavir: Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with ritonavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium [see Pharmacokinetics (12.3)] .
 
Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.
 
Saquinavir: When saquinavir is co-administered with ritonavir, consideration should be given to the potential effects of ritonavir on clarithromycin (refer to ritonavir above) [see Pharmacokinetics (12.3)] .
 
Etravirine: Clarithromycin exposure was decreased by etravirine; however, concentrations of the active metabolite, 14-OH-clarithromycin, were increased. Because 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered; therefore alternatives to clarithromycin should be considered for the treatment of MAC.
Proton Pump Inhibitors:
 
Omeprazole
 
 
Use With Caution
 
 
Omeprazole: Clarithromycin concentrations in the gastric tissue and mucus were also increased by concomitant administration of omeprazole [see Pharmacokinetics (12.3)] .
Miscellaneous Cytochrome P450 Inducers:
 
Efavirenz
Nevirapine
Rifampicin
Rifabutin
Rifapentine
 
 
 
Use With Caution
 
 
 
Inducers of CYP3A enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine will increase the metabolism of clarithromycin, thus decreasing plasma concentrations of clarithromycin, while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. Alternative antibacterial treatment should be considered when treating patients receiving inducers of CYP3A. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with rifabutin (see Rifabutin under “Drugs That Are Affected By Clarithromycin” in the table above).


Table name:
Table 4. Drugs That May Alter Hepatic Metabolism of T4 (Hypothyroidism)
Potential impact: Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased SYNTHROID requirements.
Drug or Drug Class Effect
Phenobarbital
Rifampin
Phenobarbital has been shown to reduce the response to thyroxine. Phenobarbital increases L-thyroxine metabolism by inducing uridine 5’-diphospho-glucuronosyltransferase (UGT) and leads to a lower T4 serum levels. Changes in thyroid status may occur if barbiturates are added or withdrawn from patients being treated for hypothyroidism. Rifampin has been shown to accelerate the metabolism of levothyroxine.


Table name:
Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s) Recommendation Comments
Tizanidine Contraindicated Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)].
Theophylline Avoid Use (Plasma Exposure Likely to be Increased and Prolonged) Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions (5.6).]
Drugs Known to Prolong QT Interval Avoid Use Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.10) and Use in Specific Populations (8.5)].
Oral antidiabetic drugs Use with caution Glucose-lowering effect potentiated Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported . Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs. [see Adverse Reactions (6.1).]
Phenytoin Use with caution Altered serum levels of phenytoin (increased and decreased) To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after coadministration of ciprofloxacin with phenytoin.
Cyclosporine Use with caution (transient elevations in serum creatinine) Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs Use with caution (Increase in anticoagulant effect) The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole Use with caution Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after coadministration with ciprofloxacin [see Warnings and Precautions (5.15)].
Clozapine Use with caution Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs Use with caution Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil Use with caution 2-fold increase in exposure Monitor for sildenafil toxicity (see Pharmacokinetics -(12.3)-] .
Duloxetine Avoid Use 5-fold increase in duloxetine exposure If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx ® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products) Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2)]. Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels) Potentiation of ciprofloxacin toxicity may occur.


Table name:
Table 4 Drugs Tested in In Vitro Binding or In Vivo Drug Interaction Testing or With Post-Marketing Reports
a Should be administered at least 4 hours prior to WELCHOL
b No significant alteration of warfarin drug levels with warfarin and WELCHOL coadministration in an in vivo study which did not evaluate warfarin pharmacodynamics (INR). [See Post-marketing Experience (6.2)]
c Cyclosporine levels should be monitored and, based on theoretical grounds, cyclosporine should be administered at least 4 hours prior to WELCHOL.
Drugs with a known interaction with colesevelam Cyclosporinec, glyburidea, levothyroxinea, and oral contraceptives containing ethinyl estradiol and norethindronea
Drugs with postmarketing reports consistent with potential drug-drug interactions when coadministered with WELCHOL phenytoina, warfarinb
Drugs that do not interact with colesevelam based on in vitro or in vivo testing cephalexin, ciprofloxacin, digoxin, warfarinb fenofibrate, lovastatin, metformin, metoprolol, pioglitazone, quinidine, repaglinide, valproic acid, verapamil


Table name:
CYP2C19 or CYP3A4 Inducers
Clinical Impact: Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology (12.3)].
Intervention: St. John’s Wort, rifampin: Avoid concomitant use with omeprazole [see Warnings and Precautions (5.9)].

Ritonavir-containing products: see prescribing information for specific drugs.
CYP2C19 or CYP3A4 Inhibitors
Clinical Impact: Increased exposure of omeprazole [see Clinical Pharmacology (12.3)].
  Intervention: Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered.

See prescribing information for voriconazole.


Table name:
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Table 5 Includes clinically significant drug interactions with BELBUCA.
Benzodiazepines
Clinical Impact: There have been a number of reports regarding coma and death associated with the misuse and abuse of the combination of buprenorphine and benzodiazepines. In many, but not all of these cases, buprenorphine was misused by self-injection of crushed buprenorphine tablets. Preclinical studies have shown that the combination of benzodiazepines and buprenorphine altered the usual ceiling effect on buprenorphine-induced respiratory depression, making the respiratory effects of buprenorphine appear similar to those of full opioid agonists.
Intervention: Closely monitor patients with concurrent use of BELBUCA and benzodiazepines. Warn patients that it is extremely dangerous to self-administer benzodiazepines while taking BELBUCA, and warn patients to use benzodiazepines concurrently with BELBUCA only as directed by their physician.
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.4)].
Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and other opioids, alcohol.
Inhibitors of CYP3A4
Clinical Impact: The concomitant use of buprenorphine and CYP3A4 inhibitors can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of BELBUCA is achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the buprenorphine plasma concentration will decrease [see Clinical Pharmacology (12.3)], potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to buprenorphine.
Intervention: If concomitant use is necessary, consider dosage reduction of BELBUCA until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the BELBUCA dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)
CYP3A4 Inducers
Clinical Impact: The concomitant use of buprenorphine and CYP3A4 inducers can decrease the plasma concentration of buprenorphine [see Clinical Pharmacology (12.3)], potentially resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the buprenorphine plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both therapeutic effects and adverse reactions and may cause serious respiratory depression.
Intervention: If concomitant use is necessary, consider increasing the BELBUCA dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider BELBUCA dosage reduction and monitor for signs of respiratory depression.
Examples: Rifampin, carbamazepine, phenytoin
Serotonergic Drugs
Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue BELBUCA if serotonin syndrome is suspected.
Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)].
Intervention: The use of BELBUCA is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples: phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact: May reduce the analgesic effect of BELBUCA and/or precipitate withdrawal symptoms.
Intervention: Avoid concomitant use.
Examples: butorphanol, nalbuphine, pentazocine
Muscle Relaxants
Clinical Impact: Buprenorphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention: Monitor patients receiving muscle relaxants and BELBUCA for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of BELBUCA and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact: The concomitant use of anticholinergic drugs may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when BELBUCA is used concomitantly with anticholinergic drugs.
Antiretrovirals: Nucleoside reverse transcriptase inhibitors (NRTIs)
Clinical Impact: Nucleoside reverse transcriptase inhibitors (NRTIs) do not appear to induce or inhibit the P450 enzyme pathway, thus no interactions with buprenorphine are expected.
Intervention: None
Antiretrovirals: Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Clinical Impact: Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are metabolized principally by CYP3A4. Efavirenz, nevirapine, and etravirine are known CYP3A inducers, whereas delaviridine is a CYP3A inhibitor. Significant pharmacokinetic interactions between NNRTIs (e.g., efavirenz and delavirdine) and buprenorphine have been shown in clinical studies, but these pharmacokinetic interactions did not result in any significant pharmacodynamic effects.
Intervention: Patients who are on chronic BELBUCA treatment should have their dose monitored if NNRTIs are added to their treatment regimen.
Examples: efavirenz, nevirapine, etravirine, delavirdine
Antiretrovirals: Protease inhibitors (PIs)
Clinical Impact: Studies have shown some antiretroviral protease inhibitors (PIs) with CYP3A4 inhibitory activity (nelfinavir, lopinavir/ritonavir, ritonavir) have little effect on buprenorphine pharmacokinetic and no significant pharmacodynamic effects. Other PIs with CYP3A4 inhibitory activity (atazanavir and atazanavir/ritonavir) resulted in elevated levels of buprenorphine and norbuprenorphine, and patients in one study reported increased sedation. Symptoms of opioid excess have been found in post-marketing reports of patients receiving buprenorphine and atazanavir with and without ritonavir concomitantly.
Intervention: Monitor patients taking BELBUCA and atazanavir with and without ritonavir, and dose reduction of BELBUCA may be warranted.
Examples: atazanavir, ritonavir


Table name:
Drug Interactions Associated with Increased Risk of  Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice Avoid grapefruit juice


Table name:
Drugs That Interfere with Hemostasis
Clinical Impact: • Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of naproxen or naproxen sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: Concomitant use of naproxen or naproxen sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen or naproxen sodium is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE-inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: • During concomitant use of naproxen or naproxen sodium and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of naproxen or naproxen sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen or naproxen sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact: The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of naproxen or naproxen sodium and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen or naproxen sodium and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of naproxen or naproxen sodium and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of naproxen or naproxen sodium and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of naproxen or naproxen sodium and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of naproxen or naproxen sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of naproxen or naproxen sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact: Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention: Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen or naproxen sodium is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed release tablets are not recommended.
Cholestyramine
Clinical Impact: Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention: Concomitant administration of cholestyramine with naproxen or naproxen sodium is not recommended.
Probenecid
Clinical Impact: Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention: Patients simultaneously receiving naproxen or naproxen sodium and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact: Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention: Patients simultaneously receiving naproxen or naproxen sodium and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.


Table name:
Table 8: Clinically Significant Drug Interactions with Clarithromycin
Drugs That Are Affected By Clarithromycin
Drug(s) with Pharmacokinetics Affected by Clarithromycin Recommendation Comments
Antiarrhythmics:


 
Disopyramide
Quinidine
Dofetilide
Amiodarone
Sotalol
Procainamide
Not Recommended Disopyramide, Quinidine: There have been postmarketing reports of torsades de pointes occurring with concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QTc prolongation during coadministration of clarithromycin with these drugs [see Warnings and Precautions (5.3)] .

Serum concentrations of these medications should also be monitored. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with disopyramide and quinidine.

There have been postmarketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide. Therefore, blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide.


Digoxin Use With Caution Digoxin: Digoxin is a substrate for P-glycoprotein (Pgp) and clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are co-administered, inhibition of Pgp by clarithromycin may lead to increased exposure of digoxin. Elevated digoxin serum concentrations in patients receiving clarithromycin and digoxin concomitantly have been reported in postmarketing surveillance. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Monitoring of serum digoxin concentrations should be considered, especially for patients with digoxin concentrations in the upper therapeutic range.


Oral Anticoagulants:


   
Warfarin Use With Caution Oral anticoagulants: Spontaneous reports in the postmarketing period suggest that concomitant administration of clarithromycin and oral anticoagulants may potentiate the effects of the oral anticoagulants. Prothrombin times should be carefully monitored while patients are receiving clarithromycin and oral anticoagulants simultaneously [see Warnings and Precautions (5.4)] .


Antiepileptics:


   
Carbamazepine Use With Caution Carbamazepine: Concomitant administration of single doses of clarithromycin and carbamazepine has been shown to result in increased plasma concentrations of carbamazepine. Blood level monitoring of carbamazepine may be considered. Increased serum concentrations of carbamazepine were observed in clinical trials with clarithromycin. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with carbamazepine.


Antifungals:


 
Itraconazole Use With Caution Itraconazole: Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when administered concomitantly (see also Itraconazole under “Drugs That Affect Clarithromycin” in the table below). Clarithromycin may increase the plasma concentrations of itraconazole. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions.


Fluconazole No Dose Adjustment


Fluconazole: [see Pharmacokinetics (12.3)]
Anti-Gout Agents:


 
Colchicine (in patients with renal or hepatic impairment)


Contraindicated Colchicine: Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. The dose of colchicine should be reduced when co-administered with clarithromycin in patients with normal renal and hepatic function [see Contraindications (4.4) and Warnings and Precautions (5.4)] .


Colchicine (in patients with normal renal and hepatic function) Use With Caution
Antipsychotics:


 
Pimozide Contraindicated Pimozide: [See Contraindications (4.2)]


Quetiapine Quetiapine: Quetiapine is a substrate for CYP3A4, which is inhibited by clarithromycin. Co-administration with clarithromycin could result in increased quetiapine exposure and possible quetiapine related toxicities. There have been postmarketing reports of somnolence, orthostatic hypotension, altered state of consciousness, neuroleptic malignant syndrome, and QT prolongation during concomitant administration. Refer to quetiapine prescribing information for recommendations on dose reduction if co-administered with CYP3A4 inhibitors such as clarithromycin.


Antispasmodics:


   
Tolterodine (patients deficient in CYP2D6 activity) Use With Caution Tolterodine: The primary route of metabolism for tolterodine is via CYP2D6. However, in a subset of the population devoid of CYP2D6, the identified pathway of metabolism is via CYP3A. In this population subset, inhibition of CYP3A results in significantly higher serum concentrations of tolterodine. Tolterodine 1 mg twice daily is recommended in patients deficient in CYP2D6 activity (poor metabolizers) when co-administered with clarithromycin.


Antivirals:


   
Atazanavir Use With Caution Atazanavir: Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction (see Atazanavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)] .


Saquinavir (in patients with decreased renal function)   Saquinavir: Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A and there is evidence of a bi-directional drug interaction (see Saquinavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)] .


Ritonavir
Etravirine
  Ritonavir, Etravirine: (see Ritonavir and Etravirine under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)] .


Maraviroc   Maraviroc: Clarithromycin may result in increases in maraviroc exposures by inhibition of CYP3A metabolism. See Selzentry ® prescribing information for dose recommendation when given with strong CYP3A inhibitors such as clarithromycin.


Boceprevir (in patients with normal renal function)

Didanosine
No Dose Adjustment Boceprevir: Both clarithromycin and boceprevir are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when co-administered. No dose adjustments are necessary for patients with normal renal function (see Victrelis ® prescribing information).


Zidovudine   Zidovudine: Simultaneous oral administration of clarithromycin immediate-release tablets and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine concentrations. Administration of clarithromycin and zidovudine should be separated by at least two hours [see Pharmacokinetics (12.3)] .

The impact of co-administration of clarithromycin extended-release tablets or granules and zidovudine has not been evaluated.


Calcium Channel Blockers:


   
Verapamil Use With Caution Verapamil: Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent verapamil, [see Warnings and Precautions (5.4)] .


Amlodipine
Diltiazem


  Amlodipine, Diltiazem: [See Warnings and Precautions (5.4)]
Nifedipine   Nifedipine: Nifedipine is a substrate for CYP3A. Clarithromycin and other macrolides are known to inhibit CYP3A. There is potential of CYP3A-mediated interaction between nifedipine and clarithromycin. Hypotension and peripheral edema were observed when clarithromycin was taken concomitantly with nifedipine [see Warnings and Precautions (5.4)] .


Ergot Alkaloids:


   
Ergotamine
Dihydroergotamine
Contraindicated Ergotamine, Dihydroergotamine: Postmarketing reports indicate that coadministration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system [see Contraindications (4.6)] .


Gastroprokinetic Agents:


   
Cisapride Contraindicated Cisapride: [See Contraindications (4.2)]


HMG-CoA Reductase Inhibitors:


   
Lovastatin
Simvastatin
Contraindicated Lovastatin, Simvastatin, Atorvastatin, Pravastatin, Fluvastatin: [See Contraindications (4.5) and Warnings and Precautions (5.4)]

Atorvastatin
Pravastatin


Use With Caution  
Fluvastatin

No Dose Adjustment


 
Hypoglycemic Agents:


   
Nateglinide
Pioglitazone
Repaglinide
Rosiglitazone


Use With Caution Nateglinide, Pioglitazone, Repaglinide, Rosiglitazone: [See Warnings and Precautions (5.4) and Adverse Reactions (6.2)]

Insulin   Insulin: [See Warnings and Precautions (5.4) and Adverse Reactions (6.2)]


Immunosuppressants:


   
Cyclosporine Use With Caution Cyclosporine: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with cyclosporine.


Tacrolimus   Tacrolimus: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with tacrolimus.


Phosphodiesterase inhibitors:


   
Sildenafil
Tadalafil
Vardenafil
Use With Caution Sildenafil, Tadalafil, Vardenafil: Each of these phosphodiesterase inhibitors is primarily metabolized by CYP3A, and CYP3A will be inhibited by concomitant administration of clarithromycin. Co-administration of clarithromycin with sildenafil, tadalafil, or vardenafil will result in increased exposure of these phosphodiesterase inhibitors. Co-administration of these phosphodiesterase inhibitors with clarithromycin is not recommended. Increased systemic exposure of these drugs may occur with clarithromycin; reduction of dosage for phosphodiesterase inhibitors should be considered (see their respective prescribing information).


Proton Pump Inhibitors:


   
Omeprazole No Dose Adjustment Omeprazole: The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when coadministered with clarithromycin as a result of increased omeprazole exposures [see Pharmacokinetics (12.3)] (see also Omeprazole under “Drugs That Affect Clarithromycin” in the table below).


Xanthine Derivatives:


   
Theophylline Use With Caution Theophylline: Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serum theophylline concentrations [see Pharmacokinetics (12.3)] . Monitoring of serum theophylline concentrations should be considered for patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range.


Triazolobenzodiazepines and Other Related Benzodiazepines:


   
Midazolam Use With Caution Midazolam: When oral midazolam is co-administered with clarithromycin, dose adjustments may be necessary and possible prolongation and intensity of effect should be anticipated [see Warnings and Precautions (5.4) and Pharmacokinetics (12.3)] .


Alprazolam
Triazolam
  Triazolam, Alprazolam: Caution and appropriate dose adjustments should be considered when triazolam or alprazolam is co-administered with clarithromycin. There have been postmarketing reports of drug interactions and central nervous system (CNS) effects (e.g., somnolence and confusion) with the concomitant use of clarithromycin and triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested.

In postmarketing experience, erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines.


Temazepam
Nitrazepam
Lorazepam
No Dose Adjustment Temazepam, Nitrazepam, Lorazepam: For benzodiazepines which are not metabolized by CYP3A (e.g., temazepam, nitrazepam, lorazepam), a clinically important interaction with clarithromycin is unlikely.


Cytochrome P450 Inducers:


   
Rifabutin Use With Caution Rifabutin: Concomitant administration of rifabutin and clarithromycin resulted in an increase in rifabutin, and decrease in clarithromycin serum levels together with an increased risk of uveitis (see Rifabutin under “Drugs That Affect Clarithromycin” in the table below).


Other Drugs Metabolized by CYP3A:


   
Alfentanil
Bromocriptine
Cilostazol
Methylprednisole
Vinblastine
Phenobarbital
St. John’s Wort


Use With Caution There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with alfentanil, methylprednisolone, cilostazol, bromocriptine, vinblastine, phenobarbital, and St. John’s Wort.
Other Drugs Metabolized by CYP450 Isoforms Other than CYP3A:


   
Hexobarbital
Phenytoin
Valproate
Use With Caution There have been postmarketing reports of interactions of clarithromycin with drugs not thought to be metabolized by CYP3A, including hexobarbital, phenytoin, and valproate.


Drugs that Affect Clarithromycin
Drug(s) that Affect the Pharmacokinetics of Clarithromycin Recommendation Comments
Antifungals:


   
Itraconazole

Use With Caution Itraconazole: Itraconazole may increase the plasma concentrations of clarithromycin. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions (see also Itraconazole under “Drugs That Are Affected By Clarithromycin” in the table above).


Antivirals:


   
Atazanavir Use With Caution Atazanavir: When clarithromycin is co-administered with atazanavir, the dose of clarithromycin should be decreased by 50% [see Clinical Pharmacology (12.3)] .

Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with atazanavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium complex. Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.


Ritonavir (in patients with decreased renal function)   Ritonavir: Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with ritonavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium [see Pharmacokinetics (12.3)] .

Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.


Saquinavir (in patients with decreased renal function)   Saquinavir: When saquinavir is co-administered with ritonavir, consideration should be given to the potential effects of ritonavir on clarithromycin (refer to ritonavir above) [see Pharmacokinetics (12.3)] .


Etravirine   Etravirine: Clarithromycin exposure was decreased by etravirine; however, concentrations of the active metabolite, 14-OH-clarithromycin, were increased. Because 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered; therefore alternatives to clarithromycin should be considered for the treatment of MAC.


Saquinavir (in patients with normal renal function) No Dose Adjustment  
Ritonavir (in patients with normal renal function)


   
Proton Pump Inhibitors:


   
Omeprazole Use With Caution Omeprazole: Clarithromycin concentrations in the gastric tissue and mucus were also increased by concomitant administration of omeprazole [see Pharmacokinetics (12.3)] .


Miscellaneous Cytochrome P450 Inducers:


 
Efavirenz
Nevirapine
Rifampicin
Rifabutin
Rifapentine
Use With Caution Inducers of CYP3A enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine will increase the metabolism of clarithromycin, thus decreasing plasma concentrations of clarithromycin, while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. Alternative antibacterial treatment should be considered when treating patients receiving inducers of CYP3A. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with rifabutin (see Rifabutin under “Drugs That Are Affected By Clarithromycin” in the table above).


Table name:
Interacting  Drug 
Interaction 
Multivalent cation-containing products including antacids, metal cations or didanosine 
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin 
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents 
Carefully monitor blood glucose (5.12, 7.3)


Table name:
Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme
Inhibitors
Inducers
CYP2C9 
amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast
aprepitant, bosentan, carbamazepine, phenobarbital, rifampin 
CYP1A2 
acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton
montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking 
CYP3A4 
alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton
armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide 


Table name:
Interacting Drug Interaction
Antacids, sucralfate, multivitamins, and other products containing multivalent cations Moxifloxacin absorption is decreased. Administer AVELOX Tablet at least 4 hours before or 8 hours after these products. (2.2, 7.1, 12.3, 17.2)
Warfarin Anticoagulant effect of warfarin may be enhanced. Monitor prothrombin time/INR, watch for bleeding. (6.4, 7.2, 12.3)
Class IA and Class III antiarrhythmics: Proarrhythmic effect may be enhanced. Avoid concomitant use. (5.3, 7.4)


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.11, 7.3)


Table name:
Classes of Drugs
Adrenal Cortical Steroid
Inhibitors
Antacids
Antianxiety Agents
Antiarrhythmics†
Antibiotics†
Anticonvulsants†
Antidepressants†
Antihistamines
Antineoplastics†
Antipsychotic Medications
Antithyroid Drugs†
Barbiturates
Diuretics†
Enteral Nutritional
Supplements
Fungal Medications, Systemic†
Gastric Acidity and Peptic
Ulcer Agents†
Hypnotics†
Hypolipidemics†
Bile Acid-Binding Resins†
HMG-CoA Reductase Inhibitors†
Immunosuppressives
Oral Contraceptives, Estrogen
Containing
Selective Estrogen Receptor
Modulators
Steroids, Adrenocortical†
Tuberculosis Agents†
Vitamins†


Table name:
Table 18Summary of Effect of Coadministered Drugs on Exposure to Active Moiety(Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients withSchizophrenia
*Change relative to reference
Coadministered Drug
Dosing Schedule

Effect on Active
Moiety
(Risperidone + 9-
Hydroxy-
Risperidone (Ratio*)

Risperidone Dose
Recommendation

Coadministered Drug
Risperidone
AUC
C m a x

Enzyme (CYP2D6) 
Inhibitors 





Fluoxetine 
20 mg/day
2 or 3 mg twice
daily
1.4
1.5
Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine 
10 mg/day
4 mg/day
1.3
-
Re-evaluate dosing. 

20 mg/day
4 mg/day
1.6
-
Do not exceed 8 mg/day

40 mg/day
4 mg/day
1.8
-

Enzyme (CYP3A/ 
PgP inducers) 





Carbamazepine 
573 ± 168 mg/day
3 mg twice daily
0.51
0.55
Titrate dose upwards.
Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) 
Inhibitors 





Ranitidine 
150 mg twice daily
1 mg single dose
1.2
1.4
Dose adjustment not
needed
Cimetidine 
400 mg twice daily
1 mg single dose
1.1
1.3
Dose adjustment not
needed
Erythromycin 
500 mg four times
daily
1 mg single dose
1.1
0.94
Dose adjustment not
needed
Other Drugs 





Amitriptyline 
50 mg twice daily
3 mg twice daily
1.2
1.1
Dose adjustment not
needed


Table name:
Table 2: Clinically Relevant Interactions Affecting Drugs Co-Administered with Rabeprazole Sodium Delayed-Release Tablets
Antiretrovirals 
Clinical  Impact

The effect of PPI on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. 

•  Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir, and nelfinavir) when used concomitantly with rabeprazole may reduce antiviral effect and promote the
 development of drug resistance. 

•  Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with rabeprazole may increase toxicity.

•  There are other antiretroviral drugs which do not result in clinically relevant interactions with rabeprazole. 

Rilpivirine-containing products: Concomitant use with rabeprazole sodium delayed-release tablets are contraindicated [see CONTRAINDICATIONS (4)]. See prescribing information.

Atazanavir See prescribing information for atazanavir for dosing information. 
Intervention
Nelfinavir Avoid concomitant use with rabeprazole sodium delayed-release tablets. See prescribing information for nelfinavir. 

Saquinavir See the prescribing information for saquinavir and monitor for potential saquinavir toxicities. 

Other  antiretrovirals See prescribing information. 
Warfarin 
Clinical  Impact

Increased INR and prothrombin time in patients receiving PPIs, including rabeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal  bleeding and even death [see WARNINGS AND PRECAUTIONS (5.2)].
Intervention
Monitor INR and prothrombin time. Dose adjustment of warfarin may be needed to maintain target INR range. See prescribing information for warfarin. 
Methotrexate 
Clinical  Impact

Concomitant use of rabeprazole with methotrexate (primarily at high dose) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate,  possibly leading to methotrexate toxicities. No formal drug interaction studies of methotrexate with PPIs have been conducted [see WARNINGS AND PRECAUTIONS (5.9)].
Intervention

A temporary withdrawal of rabeprazole sodium delayed-release tablets may be considered in some patients receiving high dose methotrexate administration. 
Digoxin 
Clinical  Impact
Potential for increased exposure of digoxin [see CLINICAL PHARMACOLOGY (12.3)].
Intervention
Monitor digoxin concentrations. Dose adjustment of digoxin may be needed to maintain therapeutic drug concentrations. See prescribing information for digoxin. 
Drugs  Dependent  on  Gastric  pH  for  Absorption  ( e . g .,  iron  salts erlotinib dasatinib nilotinib mycophenolate  mofetil ketoconazole itraconazole
Clinical  Impact
Rabeprazole can reduce the absorption of drugs due to its effect on reducing intragastric acidity. 
Intervention
Mycophenolate mofetil (MMF): Co-administration of PPIs in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, 
mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in 
transplant patients receiving PPIs and MMF. Use rabeprazole sodium delayed-release tablets with caution in transplant patients receiving MMF. 

See the prescribing information for other drugs dependent on gastric pH for absorption. 
Combination  Therapy  with  Clarithromycin  and  Amoxicillin 
Clinical  Impact
Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated.

Amoxicillin also has drug interactions. 
Intervention
See CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS in prescribing information for clarithromycin. See DRUG INTERACTIONS in prescribing information for amoxicillin.


Table name:
Table 1. Selected Drugs That Have Been Shown To or Are Predicted To Have Their Plasma Concentrations Altered By KetoconazoleThis list is not all-inclusive.
 Systemic exposure to these drugs is increased significantly by the addition of ketoconazole: Concomitant use with ketoconazole is contraindicated.
 Alprazolam, midazolam, triazolam  HMG-CoA reductase inhibitors (lovastatin, simvastatin)
 Cisapride  Nisoldipine
 Dofetilide  Pimozide
 Eplerenone  Quinidine
 Ergot alkaloids (ergotamine, dihydroergotamine)  
  
 Systemic exposure to these drugs is increased by ketoconazole: Careful monitoring, with possible adjustment in dosage, is recommended.
 Alfentanil, fentanyl, sulfentanil  Indinavir, saquinavir
 Amlodipine, felodipine, nicardipine, nifedipine  Methylprednisolone
 Bosentan  Rifabutin
 Buspirone  Sildenafil
 Busulfan  Sirolimus (co-administration not recommended)
 Carbamazepine  Tacrolimus
 Cilostazol  Telithromycin
 Cyclosporine  Tolterodine
 Digoxin  Trimetrexate
 Docetaxel, paclitaxel  Verapamil
 Oral anti-coagulants  Vinca alkaloids (vincristine, - vinblastine, vinorelbine)


Table name:
Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
Table 2: Drug Interactions: Pharmacokinetic Parameters for Indinavir in the Presence of the Coadministered Drug (See PRECAUTIONS, Table 9 for Recommended Alterations in Dose or Regimen)
Coadministered drug Dose of Coadministered drug (mg) Dose of CRIXIVAN
(mg)
n Ratio (with/without coadministered drug) of Indinavir
Pharmacokinetic Parameters
(90% CI); No Effect = 1.00
Cmax AUC Cmin
All interaction studies conducted in healthy, HIV-negative adult subjects, unless otherwise indicated.
Cimetidine 600 twice daily,
6 days
400 single dose 12 1.07
(0.77, 1.49)
0.98
(0.81, 1.19)
0.82
(0.69, 0.99)
Clarithromycin 500 q12h,
7 days
800 three times
daily, 7 days
10 1.08
(0.85, 1.38)
1.19
(1.00, 1.42)
1.57
(1.16, 2.12)
Delavirdine 400 three times daily 400 three times
daily, 7 days
28 0.64Relative to indinavir 800 mg three times daily alone.
(0.48, 0.86)
No significant change 2.18
(1.16, 4.12)
Delavirdine 400 three times daily 600 three times
daily, 7 days
28 No significant change 1.53
(1.07, 2.20)
3.98
(2.04, 7.78)
EfavirenzStudy conducted in HIV-positive subjects. 600 once daily,
10 days
1000 three times
daily, 10 days
20
After morning dose No significant change 0.67
(0.61, 0.74)
0.61
(0.49, 0.76)
After afternoon dose No significant change 0.63
(0.54, 0.74)
0.48
(0.43, 0.53)
After evening dose 0.71
(0.57, 0.89)
0.54
(0.46, 0.63)
0.43
(0.37, 0.50)
Fluconazole 400 once daily,
8 days
1000 three times daily, 7 days 11 0.87
(0.72, 1.05)
0.76
(0.59, 0.98)
0.90
(0.72, 1.12)
Grapefruit Juice 8 oz. 400 single dose 10 0.65
(0.53, 0.79)
0.73
(0.60, 0.87)
0.90
(0.71, 1.15)
Isoniazid 300 once daily in the morning,
8 days
800 three times daily, 7 days 11 0.95
(0.88, 1.03)
0.99
(0.87, 1.13)
0.89
(0.75, 1.06)
Itraconazole 200 twice daily,
7 days
600 three times
daily, 7 days
12 0.78
(0.69, 0.88)
0.99
(0.91, 1.06)
1.49
(1.28, 1.74)
Ketoconazole 400 once daily,
7 days
600 three times
daily, 7 days
12 0.69
(0.61, 0.78)
0.80
(0.74, 0.87)
1.29
(1.11, 1.51)
400 once daily,
7 days
400 three times
daily, 7 days
12 0.42
(0.37, 0.47)
0.44
(0.41, 0.48)
0.73
(0.62, 0.85)
Methadone 20-60 once daily in the morning,
8 days
800 three times
daily, 8 days
10 See text below for discussion of interaction.
Quinidine 200 single dose 400 single dose 10 0.96
(0.79, 1.18)
1.07
(0.89, 1.28)
0.93
(0.73, 1.19)
Rifabutin 150 once daily in the morning,
10 days
800 three times
daily, 10 days
14 0.80
(0.72, 0.89)
0.68
(0.60, 0.76)
0.60
(0.51, 0.72)
Rifabutin 300 once daily in the morning,
10 days
800 three times
daily, 10 days
10 0.75
(0.61, 0.91)
0.66
(0.56, 0.77)
0.61
(0.50, 0.75)
Rifampin 600 once daily in the morning,
8 days
800 three times
daily, 7 days
12 0.13
(0.08, 0.22)
0.08
(0.06, 0.11)
Not Done
Ritonavir 100 twice daily,
14 days
800 twice
daily, 14 days
10, 16Comparison to historical data on 16 subjects receiving indinavir alone. See text below for discussion of interaction.
Ritonavir 200 twice daily,
14 days
800 twice
daily,14 days
9, 16 See text below for discussion of interaction.
Sildenafil 25 single dose 800 three times daily 6 See text below for discussion of interaction.
St. John's wort
(Hypericum perforatum,
standardized to 0.3 % hypericin)
300 three times daily with meals,
14 days
800 three times daily 8 Not Available 0.46
(0.34, 0.58)95% CI.
0.19
(0.06, 0.33)
Stavudine (d4T) 40 twice daily,
7 days
800 three times
daily, 7 days
11 0.95
(0.80, 1.11)
0.95
(0.80, 1.12)
1.13
(0.83, 1.53)
Trimethoprim/
Sulfamethoxazole
800 Trimethoprim/
160 Sulfamethoxazole q12h, 7 days
400 four times
daily, 7 days
12 1.12
(0.87, 1.46)
0.98
(0.81, 1.18)
0.83
(0.72, 0.95)
Zidovudine 200 three times daily, 7 days 1000 three times
daily, 7 days
12 1.06
(0.91, 1.25)
1.05
(0.86, 1.28)
1.02
(0.77, 1.35)
Zidovudine/
Lamivudine
(3TC)
200/150 three times daily,
7 days
800 three times
daily, 7 days
6, 9Parallel group design; n for indinavir + coadministered drug, n for indinavir alone. 1.05
(0.83, 1.33)
1.04
(0.67, 1.61)
0.98
(0.56, 1.73)


Table name:
Table 7:Effect of Other Drugs on Voriconazole Pharmacokinetics [ see Clinical Pharmacology (12.3)]
 Drug/Drug Class
(Mechanism of Interaction by the Drug)
 Voriconazole Plasma Exposure
(Cmax and AUC after 200 mg q12h)
Recommendations for Voriconazole Dosage Adjustment/Comments
* Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg q12h voriconazole to healthy subjects
** Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects
*** Non-Nucleoside Reverse Transcriptase Inhibitors
Rifampin* and Rifabutin*
(CYP450 Induction)
Significantly Reduced Contraindicated
Efavirenz (400 mg q24h)**
(CYP450 Induction)
Significantly Reduced Contraindicated
Efavirenz (300 mg q24h)**
(CYP450 Induction)
Slight Decrease in AUCτ When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)**
(CYP450 Induction)
Significantly Reduced Contraindicated
 Low-dose Ritonavir (100 mg q12h)**
(CYP450 Induction)
Reduced  Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Carbamazepine
(CYP450 Induction)
Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction Contraindicated
Long Acting Barbiturates
(CYP450 Induction)
Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction Contraindicated
Phenytoin*
(CYP450 Induction)
Significantly Reduced Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg)
St. Johns Wort
(CYP450 inducer; P-gp inducer)
Significantly Reduced Contraindicated
Oral Contraceptives** containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition) Increased Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole** (CYP2C9, CYP2C19 and CYP3A4 Inhibition) Significantly Increased Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole.
Other HIV Protease Inhibitors
(CYP3A4 Inhibition)
In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir
In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV
protease inhibitors
Other NNRTIs***
(CYP3A4 Inhibition or CYP450 Induction)
In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to voriconazole
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure) Careful assessment of voriconazole effectiveness


Table name:
Concomitant Drug Name or Drug Class
Clinical Rationale
Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) 
The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].
With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)
The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].
With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Antihypertensive Drugs
Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.
Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.7)]. 
Benzodiazepines (e.g., lorazepam)
The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.7)]
Monitor sedation and blood pressure. Adjust dose accordingly.


Table name:
Table 3Drugs that Can Increase the Risk of Bleeding
Drug  Class
Specific  Drugs
Anticoagulants 
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin 
Antiplatelet Agents 
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine 
Nonsteroidal Anti-Inflammatory Agents 
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac 
Serotonin Reuptake Inhibitors 
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone 


Table name:
Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s)
Recommendation
Comments
Tizanidine
Contraindicated
Concomitant administration of tizanidine and ciprofloxacin  is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2) ].
Theophylline
Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)
Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate. [See Warnings and Precautions (5.9) .]
Drugs Known to Prolong QT Interval
Avoid Use
 
Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see  Warnings and Precautions (5.11) and Use in   Specific Populations (8.5) ].
Oral antidiabetic drugs
Use with caution Glucose-lowering effect potentiated
Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs. [See Adverse Reactions (6.1) .]
Phenytoin
Use with caution Altered serum levels of phenytoin
(increased and decreased)
 
To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin with phenytoin.
Cyclosporine
Use with caution (transient elevations in serum creatinine)
Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs
Use with caution (Increase in anticoagulant effect)
The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate
Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels
Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole
Use with caution
Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin [see Warnings and Precautions (5.16) ].
Clozapine
Use with caution
Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs
Use with caution
Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies in and postmarketing.
Sildenafil
Use with caution Two-fold increase in exposure
Monitor for sildenafil toxicity (see Clinical Pharmacology (12.3 )].
Duloxetine
Avoid Use
Five-fold increase in duloxetine exposure
If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives
Use with caution Reduced clearance resulting in elevated levels and prolongation
of serum half-life
Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx® (didanosine) chewable/ buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)
Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2.4)] .
Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid
Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)
Potentiation of ciprofloxacin toxicity may occur.


Table name:
albuterol,
   systemic and inhaled 
diltiazem  medroxyprogesterone   roxithromycin
   dirithromycin  methylprednisolone  sorbitol(purgative doses
 amoxicillin  enflurane  metronidazole     do not inhibit theophylline
   absorption)
  ampicillin,with or without
   sulbactam
 famotidine  metoprolol  
   felodipine  nadolol  
   finasteride  nifedipine  
 atenolol  hydrocortisone  nizatidine  sucralfate
 azithromycin  isoflurane  norfloxacin  terbutaline, systemic
 caffeine,dietary ingestion  isoniazid  ofloxacin  terfenadine
   isradipine  omeprazole  tetracycline
 cefaclor  influenza vaccine  prednisone  tocainide
     prednisolone  
co-trimoxazole(trimethoprim and
  sulfamethoxazole)
 ketoconazole  mebendazole  ranitidine
   lomefloxacin  rifabutin  


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 9:      Predicted Drug Interactions with VIDEX
Drug or Drug Class Effect Clinical Comment
↑  Indicates increase.
↓  Indicates decrease.
a  Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that cause pancreatic toxicity is required, suspension of VIDEX is recommended [ see Warnings and Precautions (5.1) ].
b  [ See Warnings and Precautions (5.6) .]
Drugs that may cause pancreatic toxicity ↑ risk of pancreatitis Use only with extreme cautiona
Neurotoxic drugs ↑ risk of neuropathy Use with cautionb
Antacids containing magnesium or aluminum ↑ side effects associated with antacid components Use caution with VIDEX Pediatric Powder for Oral Solution
Azole antifungals ↓ ketoconazole or itraconazole concentration Administer drugs such as ketoconazole or itraconazole at least 2 hours before VIDEX.
Quinolone antibiotics (see also ciprofloxacin in Table 8) ↓ quinolone concentration Consult package insert of the quinolone.
Tetracycline antibiotics ↓ antibiotic concentration Consult package insert of the tetracycline.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 7.8, 12.3)
Interacting Agents Prescribing Recommendations
 Strong CYP3A4 Inhibitors, (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol  Contraindicated with ezetimibe and simvastatin tablets
 Verapamil, diltiazem, dronedarone  Do not exceed 10 mg/10 mg ezetimibe and simvastatin tablets daily
 Amiodarone, amlodipine, ranolazine  Do not exceed 10 mg/20 mg ezetimibe and simvastatin tablets daily
 Lomitapide  For patients with HoFH, do not exceed 10 mg/20 mg ezetimibe and simvastatin tablets daily 
 Grapefruit juice  Avoid grapefruit juice


Table name:
Bleeding times
Clinical Impact: Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention: This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact: The administration of naproxen may result in increased urinary values for 17 ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention: Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact: Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention: This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.


Table name:
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)   Avoid atorvastatin  
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) Do not exceed 40 mg atorvastatin daily


Table name:
a Should be administered at least 4 hours prior to WELCHOL
b No significant alteration of warfarin drug levels with warfarin and WELCHOL coadministration in an in vivo study which did not evaluate warfarin pharmacodynamics (INR). [See Post-marketing Experience (6.2)]
c Cyclosporine levels should be monitored and, based on theoretical grounds, cyclosporine should be administered at least 4 hours prior to WELCHOL.
d Patients receiving concomitant metformin ER and colesevelam should be monitored for clinical response as is usual for the use of anti-diabetes drugs.
Table 4 Drugs Tested in In Vitro Binding or In Vivo Drug Interaction Testing or With Post-Marketing Reports
Drugs with a known interaction with colesevelam:
Decrease in exposure of coadministered drug
cyclosporinec, glimepiridea, glipizidea, glyburidea,
levothyroxinea, olmesartan medoxomila, and oral
contraceptives containing ethinyl estradiol and
norethindronea
Drugs with a known interaction with colesevelam:
Increase in exposure of coadministered drug
metformin extended release (ER)d
Drug(s) with postmarketing reports consistent with
potential drug-drug interactions when
coadministered with WELCHOL
phenytoina, warfarinb
Drugs that do not interact with colesevelam based
on in vitro or in vivo testing
aspirin, atenolol, cephalexin, ciprofloxacin,
digoxin, enalapril, fenofibrate, lovastatin,
metformin, metoprolol, phenytoina, pioglitazone,
rosiglitazone, quinidine, repaglinide, sitagliptin,
valproic acid, verapamil, warfarinb


Table name:
TABLE 5: Summary of Effect of Coadministered Drugs on Exposure to Asenapine in Healthy Volunteers
Coadministered drug (Postulated effect on CYP450/UGT) Dose schedules Effect on asenapine pharmacokinetics Recommendation
Coadministered drug Asenapine Cmax AUC0–∞
Fluvoxamine
(CYP1A2 inhibitor)
25 mg twice daily for 8 days 5 mg Single Dose +13% +29% Coadminister with cautionThe full therapeutic dose of fluvoxamine would be expected to cause a greater increase in asenapine plasma concentrations. AUC: Area under the curve.
Paroxetine
(CYP2D6 inhibitor)
20 mg once daily for 9 days 5 mg Single Dose –13% –9% No SAPHRIS dose adjustment required [see Drug Interactions (7.2)]
Imipramine (CYP1A2/2C19/3A4 inhibitor) 75 mg Single Dose 5 mg Single Dose +17% +10% No SAPHRIS dose adjustment required
Cimetidine (CYP3A4/2D6/1A2 inhibitor) 800 mg twice daily for 8 days 5 mg Single Dose –13% +1% No SAPHRIS dose adjustment required
Carbamazepine
(CYP3A4 inducer)
400 mg twice daily for 15 days 5 mg Single Dose –16% –16% No SAPHRIS dose adjustment required
Valproate
(UGT1A4 inhibitor)
500 mg twice daily for 9 days 5 mg Single Dose 2% –1% No SAPHRIS dose adjustment required


Table name:
Summary of antiepileptic drug (AED) interactions with topiramate (7.1).
 AED co-administered  AED Concentration  Topiramate Concentration
 Phenytoin  NC or 25% increasePlasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.  48% decrease
 Carbamazaepine (CBZ)  NC  40% decrease
 CBZ epoxideIs not administered but is an active metabolite of carbamazepine  NC  NE
 Valproic acid  11% decrease  14% decrease
 Phenobarbital  NC  NE
 Primidone  NC  NE
 Lamotrigine  NC at TPM doses up to 400mg/day  13% decrease


Table name:
Table 2: Drug-Thyroidal Axis Interactions
  Drug or Drug Class   Effect
  Drugs that may reduce TSH secretion–the reduction is not sustained; therefore, hypothyroidism does not occur
  Dopamine / Dopamine Agonists
Glucocorticoids
Octreotide
  Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day).
  Drugs that alter thyroid hormone secretion
  Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
  Aminoglutethimide
Amiodarone
Iodide(including iodine-containing
  Radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
  Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients.  The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
  Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
  Amiodarone
Iodide(including iodine-containing   
  Radiographic contrast agents)
  Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma).  Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
  Drugs that may decrease T4 absorption, which may result in hypothyroidism
  Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
  Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism.  Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents.  Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
  Drugs that may alter T4 and T3 serum transport  - but FT4 concentration remains normal; and, therefore, the patient remains euthyroid
  Drugs that may increase serum TBG concentration   Drugs that may decrease serum TBG concentration
  Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
  Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
  Drugs that may cause protein-binding site displacement
  Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
  Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4, and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
  Drugs that may alter T4 and T3 metabolism
  Drugs that may increase hepatic metabolism, which may result  in hypothyroidism
  Carbamazepine
Hydantoins
Phenobarbital
Rifampin
  Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
  Drugs that may decrease T4 5’-deiodinase activity
  Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
  Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4  levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
  Miscellaneous
  Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
  Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
  Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors
  (SSRIs; e.g., Sertraline)
  Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of  tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
  Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
  Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
  Cardiac Glycosides   Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
  Cytokines
- Interferon-α
- Interleukin-2
  Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
  Growth Hormones
- Somatrem
- Somatropin
  Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
  Ketamine   Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
  Methylxanthine Bronchodilators
- (e.g., Theophylline)
  Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
  Radiographic Agents   Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
  Sympathomimetics   Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
  Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
  These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.


Table name:
Interacting Drug Interaction
Drugs known to prolong QT interval (e.g., Class IA and Class III antiarrhythmic agents). Quinine sulfate capsules, USP prolongs QT interval, ECG abnormalities including QT prolongation and Torsades de Pointes. Avoid concomitant use ( 5.3).
Other antimalarials (e.g., halofantrine, mefloquine). ECG abnormalities including QT prolongation. Avoid concomitant use ( 5.3, 7.2).
CYP3A4 inducers or inhibitors Alteration in plasma quinine concentration. Monitor for lack of efficacy or increased adverse events of quinine ( 7.1).
CYP3A4 and CYP2D6 substrates Quinine is an inhibitor of CYP3A4 and CYP2D6. Monitor for lack of efficacy or increased adverse events of the co-administered drug ( 7.2).
Digoxin Increased digoxin plasma concentration ( 5.8, 7.1).


Table name:
Table 4: Clinically Important Drug Interactions with VIIBRYD
Concomitant Drug Name or Drug Class Clinical Rationale Clinical Recommendation
Monoamine Oxidase Inhibitors (MAOIs) The concomitant use of MAOIs and serotonergic drugs including VIIBRYD increases the risk of serotonin syndrome. VIIBRYD is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [see Contraindications (4), Dosage and Administration (2.3), and Warnings and Precautions (5.2)].
Other Serotonergic Drugs The concomitant use of serotonergic drugs including VIIBRYD and other serotonergic drugs increases the risk of serotonin syndrome. Monitor patients for signs and symptoms of serotonin syndrome, particularly during VIIBRYD initiation. If serotonin syndrome occurs, consider discontinuation of VIIBRYD and/or concomitant serotonergic drugs [see Warnings and Precautions (5.2)].
Antiplatelet Agents and Anticoagulants Serotonin release by platelets plays an important role in hemostasis. The concurrent use of an antiplatelet agent or anticoagulant with VIIBRYD may potentiate the risk of bleeding. Inform patients of the increased risk of bleeding with the concomitant use of VIIBRYD and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio (INR) when initiating or discontinuing VIIBRYD [see Warnings and Precautions (5.3)].
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin, voriconazole) The concomitant use of VIIBRYD and strong CYP3A4 inhibitors increased the exposure of vilazodone compared to the use of VIIBRYD alone [see Clinical Pharmacology (12.3)]. The VIIBRYD dose should not exceed 20 mg once daily with the concomitant use of a strong CYP3A4 inhibitor [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].
Strong CYP3A4 Inducers (e.g.,
carbamazepine, phenytoin, rifampin)
The concomitant use of VIIBRYD and strong CYP3A4 inducers decreased the exposure of vilazodone compared to the use of VIIBRYD alone [see Clinical Pharmacology (12.3)]. Based on clinical response, consider increasing the dosage of VIIBRYD, over 1 to 2 weeks in patients taking strong CYP3A4 inducers for greater than 14 days [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].
Digoxin Digoxin is a narrow therapeutic index drug. Concomitant use of VIIBRYD increased digoxin concentrations [see Clinical Pharmacology (12.3)]. Measure serum digoxin concentrations before initiating concomitant use of VIIBRYD. Continue monitoring and reduce digoxin dose as necessary.


Table name:
  a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
b = Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated
AED Co-administered 
AED Concentration
Topiramate Concentration
Phenytoin 
NC or 25% increasea
48% decrease
Carbamazepine (CBZ)
NC 
40% decrease
CBZ epoxideb
NC
NE
Valproic acid 
11% decrease
14% decrease
Phenobarbital
NC
NE
Primidone 
NC
NE
Lamotrigine 
NC at TPM doses up to 400 mg/day
13% decrease


Table name:
LABORATORY TESTS EFFECT OF SALICYLATES
Thyroid Function Decreased PBI; increased T3 uptake.
Urinary Sugar False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5g q.d.).
5-Hydroxyindole acetic acid False negative with fluorometric test.
Acetone, ketone bodies False positive FeCl3 in Gerhardt reaction; red color persists with boiling.
17-OH corticosteroids False reduced values with >4.8g q.d. salicylate.
Vanilmandelic acid False reduced values.
Uric acid May increase or decrease depending on dose.
Prothrombin Decreased levels; slightly increased prothrombin time.


Table name: Drugs That Are Affected By ClarithromycinDrug(s) with Pharmacokinetics Affected by ClarithromycinRecommendationComments Antiarrhythmics Disopyramide Quinidine Dofetilide Amiodarone Sotalol ProcainamideNot Recommended Disopyramide, Quinidine: There have been postmarketing reports of torsades de pointes occurring with concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QTc prolongation during coadministration of clarithromycin with these drugs [see Warnings and Precautions ( 5.3 )]. Serum concentrations of these medications should also be monitored. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with disopyramide and quinidine. There have been postmarketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide. Therefore, blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide.DigoxinUse With Caution Digoxin: Digoxin is a substrate for P-glycoprotein (Pgp) and clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are co‑ administered, inhibition of Pgp by clarithromycin may lead to increased exposure of digoxin. Elevated digoxin serum concentrations in patients receiving clarithromycin and digoxin concomitantly have been reported in postmarketing surveillance. Somepatients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Monitoring of serum digoxin concentrations should be considered, especially for patients with digoxin concentrations in the upper therapeutic range. Oral Anticoagulants WarfarinUse With CautionOral anticoagulants: Spontaneous reports in the postmarketing period suggest that concomitant administration of clarithromycin and oral anticoagulants may potentiate the effects of the oral anticoagulants. Prothrombin times should be carefully monitored while patients are receiving clarithromycin and oral anticoagulants simultaneously [see Warnings and Precautions ( 5.4 )]. Antiepileptics CarbamazepineUse With Caution Carbamazepine: Concomitant administration of single doses of clarithromycin and carbamazepine has been shown to result in increased plasma concentrations of carbamazepine. Blood level monitoring of carbamazepine may be considered. Increased serum concentrations of carbamazepine were observed in clinical trials with clarithromycin. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with carbamazepine. Antifungals ItraconazoleUse With CautionItraconazole: Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when administered concomitantly (see also Itraconazole under “Drugs That Affect Clarithromycin” in the table below). Clarithromycin may increase the plasma concentrations of itraconazole. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions.FluconazoleNo Dose Adjustment Fluconazole: [see Pharmacokinetics ( 12.3 )] Anti-Gout Agents Colchicine (in patients with renal or hepatic impairment)Contraindicated Colchicine: Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. Colchicine (in patients with normal renal and hepatic function)Use With CautionThe dose of colchicine should be reduced when co-administered with clarithromycin in patients with normal renal and hepatic function [see Contraindications ( 4.4 ) and Warnings and Precautions ( 5.4 )].Pimozide QuetiapineContraindicated Pimozide: [see Contraindications ( 4.2 )] Quetiapine: Quetiapine is a substrate for CYP3A4, which is inhibited by clarithromycin. Co‑ administration with clarithromycin could result in increased quetiapine exposure and possible quetiapine related toxicities. There have been postmarketing reports of somnolence, orthostatic hypotension, altered state of consciousness, neuroleptic malignant syndrome, and QT prolongation during concomitant administration. Refer to quetiapine prescribing information for recommendations on dose reduction if co‑ administered with CYP3A4 inhibitors such as clarithromycin. Antispasmodics : Tolterodine (patients deficient in CYP2D6 activity)Use With Caution Tolterodine: The primary route of metabolism for tolterodine is via CYP2D6. However, in a subset of the population devoid of CYP2D6, the identified pathway of metabolism is via CYP3A. In this population subset, inhibition of CYP3A results in significantly higher serum concentrations of tolterodine. Tolterodine 1 mg twice daily is recommended in patients deficient in CYP2D6 activity (poor metabolizers) when co-administered with clarithromycin. Antivirals AtazanavirUse With Caution Atazanavir: Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction (see Atazanavir under “Drugs That Affect” in the table below) [see Pharmacokinetics ( 12.3 )].Saquinavir (in patients with decreased renal function) Saquinavir: Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A and there is evidence of a bi-directional drug interaction (see Saquinavir under “Drugs That Affect” in the table below) [see Pharmacokinetics ( 12.3 )].Ritonavir, Etravirine Ritonavir, Etravirine: (see Ritonavir and Etravirine under “Drugs That Affect” in the table below) [see Pharmacokinetics ( 12.3 )].Maraviroc Maraviroc: Clarithromycin may result in increases in maraviroc exposures by inhibition of CYP3A metabolism. See Selzentry® prescribing information for dose recommendation when given with strong CYP3A inhibitors such as clarithromycin.Boceprevir (in patients with normal renal function)No Dose AdjustmentBoceprevir: Both clarithromycin and boceprevir are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when co‑ administered. No dose adjustments are necessary for patients with normal renal function (see Victrelis® prescribing information).ZidovudineZidovudine: Simultaneous oral administration of clarithromycin immediate-release tablets and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine concentrations. Administration of clarithromycin and zidovudine should be separated by at least two hours [see Pharmacokinetics ( 12.3 )]. The impact of co-administration of clarithromycin extended-release tablets or granules and zidovudine has not been evaluated. Calcium Channel Blockers VerapamilUse With Caution Verapamil: Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent verapamil [see Warnings and Precautions ( 5.4 )].Amlodipine, DiltiazemAmlodipine, Diltiazem: [See Warnings and Precautions ( 5.4 )]Nifedipine Nifedipine: Nifedipine is a substrate for CYP3A. Clarithromycin and other macrolides are known to inhibit CYP3A. There is potential of CYP3A‑ mediated interaction between nifedipine and clarithromycin. Hypotension and peripheral edema were observed when clarithromycin was taken concomitantly with nifedipine [see Warnings and Precautions ( 5.4 )]. Ergot Alkaloids Ergotamine DihydroergotamineContraindicated Ergotamine, Dihydroergotamine: Postmarketing reports indicate that coadministration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system [see Contraindications ( 4.6 )]. Gastroprokinetic Agents Cisapride HMG-CoA Reductase Inhibitor Lovastatin SimvastatinContraindicatedLovastatin, Simvastatin, Atorvastatin, Pravastatin,Fluvastatin: [See Contraindications ( 4.5 ) and Warnings and Precautions ( 5.4 )]Atorvastatin PravastatinUse With CautionFluvastatinNo Dose Adjustment Hypoglycemic Agents Nateglinide Pioglitazone Repaglinide RosiglitazoneUse With Caution Nateglinide, Pioglitazone, Repaglinide, Rosiglitazone: [see Warnings and Precautions ( 5.4 ) and Adverse Reactions ( 6.2)]Insulin Insulin: [see Warnings and Precautions ( 5.4 ) and Adverse Reactions ( 6.2 )] Immunosuppressants CyclosporineUse With Caution Cyclosporine: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with cyclosporine.Tacrolimus Tacrolimus: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with tacrolimus. Phosphodiesterase inhibitors Sildenafil Tadalafil VardenafilUse With Caution Sildenafil, Tadalafil, Vardenafil: Each of these phosphodiesterase inhibitors is primarily metabolized by CYP3A, and CYP3A will be inhibited by concomitant administration of clarithromycin. Co-administration of clarithromycin with sildenafil, tadalafil, or vardenafil will result in increased exposure of these phosphodiesterase inhibitors. Co-administration of these phosphodiesterase inhibitors with clarithromycin is not recommended. Increased systemic exposure of these drugs may occur with clarithromycin; reduction of dosage for phosphodiesterase inhibitors should be considered (see their respective prescribing information). Proton Pump Inhibitors OmeprazoleNo Dose AdjustmentOmeprazole: The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when coadministered with clarithromycin as a result of increased omeprazole exposures [seePharmacokinetics ( 12.3 )](see also Omeprazole under “Drugs That Affect” in the table below). Xanthine Derivatives TheophyllineUse With Caution Theophylline: Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serum theophylline concentrations [see Pharmacokinetics ( 12.3 )]. Monitoring of serum theophylline concentrations should be considered for patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range. Triazolobenzodiazepines and Other Related Benzodiazepines MidazolamUse With Caution Midazolam: When oral midazolam is co‑ administered with clarithromycin, dose adjustments may be necessary and possible prolongation and intensity of effect should be anticipated [see Warnings and Precautions ( 5.4 ) and Pharmacokinetics ( 12.3 )].Alprazolam Triazolam Triazolam, Alprazolam: Caution and appropriate dose adjustments should be considered when triazolam or alprazolam is co-administered with clarithromycin. There have been postmarketing reports of drug interactions and central nervous system (CNS) effects (e.g., somnolence and confusion) with the concomitant use of clarithromycin and triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested. In postmarketing experience, erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines.Temazepam Nitrazepam LorazepamNo Dose Adjustment Temazepam, Nitrazepam, Lorazepam: For benzodiazepines which are not metabolized by CYP3A (e.g., temazepam, nitrazepam, lorazepam), a clinically important interaction with clarithromycin is unlikely. Cytochrome P450 Inducers RifabutinUse With Caution Rifabutin: Concomitant administration of rifabutin and clarithromycin resulted in an increase in rifabutin, and decrease in clarithromycin serum levels together with an increased risk of uveitis (see Rifabutin under “Drugs That Affect” in the table below). Other Drugs Metabolized by CYP3A Alfentanil Bromocriptine Cilostazol Vinblastine Methylprednisole Phenobarbital St. John’s WortUse With CautionThere have been spontaneous or published reports of CYP3A based interactions of clarithromycin with alfentanil, methylprednisolone, cilostazol, bromocriptine, vinblastine, phenobarbital, and St. John’s Wort. Other Drugs Metabolized by CYP450 Isoforms Other than CYP3A Hexobarbital Phenytoin ValproateUse With CautionThere have been postmarketing reports of interactions of clarithromycin with drugs not thought to be metabolized by CYP3A, including hexobarbital, phenytoin, and valproateDrugs that Affect ClarithromycinDrug(s) that Affect the Pharmacokinetics of ClarithromycinRecommendationComments Antifungals ItraconazoleUse With Caution Itraconazole: Itraconazole may increase the plasma concentrations of clarithromycin. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions (see also Itraconazole under “Drugs That Are Affected By clarithromycin” in the table above). Antivirals AtazanavirUse With Caution Atazanavir: When clarithromycin is co-administered with atazanavir, the dose of clarithromycin should be decreased by 50% [see Clinical Pharmacology( 12.3 )]. Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co‑ administered with atazanavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium complex. Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.Ritonavir (in patients with decreased renal function) Ritonavir: Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with ritonavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium [see Pharmacokinetics ( 12.3 )]. Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.Saquinavir (in patients with decreased renal function) Saquinavir: When saquinavir is co-administered with ritonavir, consideration should be given to the potential effects of ritonavir on clarithromycin (refer to ritonavir above) [see Pharmacokinetics ( 12.3 )].Etravirine Etravirine: Clarithromycin exposure was decreased by etravirine; however, concentrations of the active metabolite, 14-OH-clarithromycin, were increased. Because 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered; therefore alternatives to clarithromycin should be considered for the treatment of MAC.Saquinavir (in patients with normal renal function) Ritonavir (in patients with normal renal function)No Dose Adjustment Proton Pump Inhibitors OmeprazoleUse With Caution Omeprazole: Clarithromycin concentrations in the gastric tissue and mucus were also increased by concomitant administration of omeprazole [seePharmacokinetics ( 12.3 )] Miscellaneous Cytochrome P450 Inducers Efavirenz Nevirapine Rifampicin Rifabutin RifapentineUse With CautionInducers of CYP3A enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine will increase the metabolism of clarithromycin, thus decreasing plasma concentrations of clarithromycin, while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. Alternative antibacterial treatment should be considered when treating patients receiving inducers of CYP3A. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with rifabutin (see Rifabutin under “Drugs That Are Affected By clarithromycin” in the table above).
 
 
 
 
 
           
   
                 
 
 
 
   
 
 
 
 
 
 
   
 
 
 
 
 
 
     
 
   
     
 
   
Antipsychotics
   
 
   
     
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
   
   
 
 
 
 
   
 
 
 
   
 
 
 
 
Contraindicated Cisapride: [see Contraindications ( 4.2 )]
 
   
 
 
   
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
     
 
 
 
 
   
 
 
 
 
 
 
 
 
 
   
   
     
   
 
 
 
 
 
 
             
 
 
 
     
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
   
 
 
 
 
 
 
         
 
 


Table name:
Interacting  Drug 
Interaction 
Multivalent cation-containing products including antacids, metal cations or didanosine 
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. Do not coadminister the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin 
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents 
Carefully monitor blood glucose (5.11, 7.3)


Table name:
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.Refer to PRECAUTIONS, Drug Interactions for information regarding table.
 albuterol, systemic and inhaled  medroxyprogesterone
 amoxicillin  methylprednisolone
 ampicillin, with or without sulbactam  metronidazole
 atenolol  metoprolol
 azithromycin  nadolol
 caffeine, dietary ingestion  nifedipine
 cefaclor  nizatidine
 co-trimoxazole  norfloxacin
   (trimethoprim and sulfamethoxazole)  ofloxacin
 diltiazem  omeprazole
 dirithromycin  prednisone, prednisolone
 enflurane  ranitidine
 famotidine  rifabutin
 felodipine  roxithromycin
 finasteride  sorbitol
 hydrocortisone    (purgative doses do not inhibit
 isoflurane      theophylline absorption)
 isoniazid  sucralfate
 isradipine  terbutaline, systemic
 influenza vaccine  terfenadine
 ketoconazole  tetracycline
 lomefloxacin  tocainide
 mebendazole  


Table name:
Table 2: Drug Interactions: Pharmacokinetic Parameters for Indinavir in the Presence of the Coadministered Drug (See PRECAUTIONS, Table 9 for Recommended Alterations in Dose or Regimen)
Coadministered drug Dose of Coadministered drug (mg) Dose of CRIXIVAN
(mg)
n Ratio (with/without coadministered drug) of Indinavir
Pharmacokinetic Parameters
(90% CI); No Effect = 1.00
Cmax AUC Cmin
All interaction studies conducted in healthy, HIV-negative adult subjects, unless otherwise indicated.
Cimetidine 600 twice daily,
6 days
400 single dose 12 1.07
(0.77, 1.49)
0.98
(0.81, 1.19)
0.82
(0.69, 0.99)
Clarithromycin 500 q12h,
7 days
800 three times
daily, 7 days
10 1.08
(0.85, 1.38)
1.19
(1.00, 1.42)
1.57
(1.16, 2.12)
Delavirdine 400 three times daily 400 three times
daily, 7 days
28 0.64Relative to indinavir 800 mg three times daily alone.
(0.48, 0.86)
No significant change 2.18
(1.16, 4.12)
Delavirdine 400 three times daily 600 three times
daily, 7 days
28 No significant change 1.53
(1.07, 2.20)
3.98
(2.04, 7.78)
EfavirenzStudy conducted in HIV-positive subjects. 600 once daily,
10 days
1000 three times
daily, 10 days
20
After morning dose No significant change 0.67
(0.61, 0.74)
0.61
(0.49, 0.76)
After afternoon dose No significant change 0.63
(0.54, 0.74)
0.48
(0.43, 0.53)
After evening dose 0.71
(0.57, 0.89)
0.54
(0.46, 0.63)
0.43
(0.37, 0.50)
Fluconazole 400 once daily,
8 days
1000 three times daily, 7 days 11 0.87
(0.72, 1.05)
0.76
(0.59, 0.98)
0.90
(0.72, 1.12)
Grapefruit Juice 8 oz. 400 single dose 10 0.65
(0.53, 0.79)
0.73
(0.60, 0.87)
0.90
(0.71, 1.15)
Isoniazid 300 once daily in the morning,
8 days
800 three times daily, 7 days 11 0.95
(0.88, 1.03)
0.99
(0.87, 1.13)
0.89
(0.75, 1.06)
Itraconazole 200 twice daily,
7 days
600 three times
daily, 7 days
12 0.78
(0.69, 0.88)
0.99
(0.91, 1.06)
1.49
(1.28, 1.74)
Ketoconazole 400 once daily,
7 days
600 three times
daily, 7 days
12 0.69
(0.61, 0.78)
0.80
(0.74, 0.87)
1.29
(1.11, 1.51)
400 once daily,
7 days
400 three times
daily, 7 days
12 0.42
(0.37, 0.47)
0.44
(0.41, 0.48)
0.73
(0.62, 0.85)
Methadone 20-60 once daily in the morning,
8 days
800 three times
daily, 8 days
10 See text below for discussion of interaction.
Quinidine 200 single dose 400 single dose 10 0.96
(0.79, 1.18)
1.07
(0.89, 1.28)
0.93
(0.73, 1.19)
Rifabutin 150 once daily in the morning,
10 days
800 three times
daily, 10 days
14 0.80
(0.72, 0.89)
0.68
(0.60, 0.76)
0.60
(0.51, 0.72)
Rifabutin 300 once daily in the morning,
10 days
800 three times
daily, 10 days
10 0.75
(0.61, 0.91)
0.66
(0.56, 0.77)
0.61
(0.50, 0.75)
Rifampin 600 once daily in the morning,
8 days
800 three times
daily, 7 days
12 0.13
(0.08, 0.22)
0.08
(0.06, 0.11)
Not Done
Ritonavir 100 twice daily,
14 days
800 twice
daily, 14 days
10, 16Comparison to historical data on 16 subjects receiving indinavir alone. See text below for discussion of interaction.
Ritonavir 200 twice daily,
14 days
800 twice
daily,14 days
9, 16 See text below for discussion of interaction.
Sildenafil 25 single dose 800 three times daily 6 See text below for discussion of interaction.
St. John's wort
(Hypericum perforatum,
standardized to 0.3 % hypericin)
300 three times daily with meals,
14 days
800 three times daily 8 Not Available 0.46
(0.34, 0.58)95% CI.
0.19
(0.06, 0.33)
Stavudine (d4T) 40 twice daily,
7 days
800 three times
daily, 7 days
11 0.95
(0.80, 1.11)
0.95
(0.80, 1.12)
1.13
(0.83, 1.53)
Trimethoprim/
Sulfamethoxazole
800 Trimethoprim/
160 Sulfamethoxazole q12h, 7 days
400 four times
daily, 7 days
12 1.12
(0.87, 1.46)
0.98
(0.81, 1.18)
0.83
(0.72, 0.95)
Zidovudine 200 three times daily, 7 days 1000 three times
daily, 7 days
12 1.06
(0.91, 1.25)
1.05
(0.86, 1.28)
1.02
(0.77, 1.35)
Zidovudine/
Lamivudine
(3TC)
200/150 three times daily, 7 days 800 three times
daily, 7 days
6, 9Parallel group design; n for indinavir + coadministered drug, n for indinavir alone. 1.05
(0.83, 1.33)
1.04
(0.67, 1.61)
0.98
(0.56, 1.73)


Table name:
Interacting  Drug 
Interaction 
Multivalent cation-containing products including antacids, metal cations or didanosine 
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin 
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents 
Carefully monitor blood glucose (5.11, 7.3)


Table name:
Factors
Dosage Adjustments for Aripiprazole Tablets
Known CYP2D6 Poor Metabolizers
Administer half of usual dose
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors
Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors
Administer half of usual dose
Strong CYP2D6 and CYP3A4
inhibitors
Administer a quarter of usual dose
Strong CYP3A4 inducers
Double usual dose over 1 to 2 weeks


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.11, 7.3)


Table name:
Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s) Recommendation Comments
Tizanidine Contraindicated Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [ see Contraindications (4.2) ] .
Theophylline Avoid Use
(Plasma Exposure Likely to be
Increased and Prolonged)
Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [ s ee Warnings and Precautions (5.9) ] .
Drugs Known to
Prolong QT Interval
Avoid Use Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.11) and Use in Specific Populations (8.5) ].
Oral antidiabetic drugs Use with caution
Glucose-lowering effect potentiated
Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were coadministered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is coadministered with oral antidiabetic drugs [ s ee Adverse Reactions (6.1) ] .
Phenytoin Use with caution
Altered serum levels of phenytoin (increased and decreased)
To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after coadministration of ciprofloxacin with phenytoin.
Cyclosporine Use with caution
(transient elevations in serum creatinine)
Monitor renal function (in particular serum creatinine) when ciprofloxacin is coadministered with cyclosporine.
Anti-coagulant drugs Use with caution
(Increase in anticoagulant effect)
The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after coadministration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate Use with caution
Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels
Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole Use with caution Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after coadministration with ciprofloxacin [see Warnings and Precautions (5.16) ].
Clozapine Use with caution Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after coadministration with ciprofloxacin are advised.
NSAIDs Use with caution Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil Use with caution
Two-fold increase in exposure
Monitor for sildenafil toxicity [ s ee   C li n ic a l
Pha r m a c o l og y   ( 1 2 .3)].
Duloxetine Avoid Use
Five-fold increase in duloxetine exposure
If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine
Derivatives
Use with caution
Reduced clearance resulting in elevated levels and prolongation of serum half-life
Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate,
Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx®
(didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)
Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration  (2.4) ]. Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid Use with caution
(interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)
Potentiation of ciprofloxacin toxicity may occur.


Table name:

Figure 7: Mean Standing Systolic Blood Pressure Change from Baseline


Table name:
Drug Description
Corticosteroids Decreases plasma salicylate level; Tapering doses of steroids may promote salicylism
Ammonium Sulfate Increases plasma salicylate level


Table name:
 Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
 Interacting Agents  Prescribing Recommendations
 Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)  Avoid atorvastatin
 HIV protease inhibitor (lopinavir plus ritonavir)  Use with caution and lowest dose necessary
 Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)  Do not exceed 20 mg atorvastatin daily
 HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
 Do not exceed 40 mg atorvastatin daily


Table name: Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology (12.3)]. Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see Clinical Pharmacology (12.3)]. There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole.
Table 3: Clinically Relevant Interactions Affecting Drugs Co-Administered with Omeprazole and Interaction with Diagnostics
Antiretrovirals
Clinical Impact:
The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known.
Intervention:
Rilpivirine-containing products: Concomitant use with omeprazole is contraindicated [see Contraindications (4)].
 
Atazanavir: Avoid concomitant use with omeprazole. See prescribing information for atazanavir for dosing information.
 
Nelfinavir: Avoid concomitant use with omeprazole. See prescribing information for nelfinavir.
 
Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities.
 
Other antiretrovirals: See prescribing information for specific antiretroviral drugs.
Warfarin
Clinical Impact:
Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
Intervention:
Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range.
Methotrexate
Clinical Impact:
Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions (5.11)].
Intervention:
A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate.
CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam)
Clopidogrel
Clinical Impact:
Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology (12.3)].
There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel.
Intervention:
Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy [see Warnings and Precautions (5.6)].
Citalopram
Clinical Impact:
Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology (12.3)].
Intervention:
Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.
Cilostazol
Clinical Impact:
Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology (12.3)].
Intervention:
Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.
Phenytoin
Clinical Impact:
Potential for increased exposure of phenytoin.
Intervention:
Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin.
Diazepam
Clinical Impact:
Increased exposure of diazepam [see Clinical Pharmacology (12.3)].
Intervention:
Monitor patients for increased sedation and reduce the dose of diazepam as needed.
Digoxin
Clinical Impact:
Potential for increased exposure of digoxin [see Clinical Pharmacology (12.3)].
Intervention:
Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)
Clinical Impact:
Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
Intervention:
Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF [see Clinical Pharmacology (12.3)].
 
See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact:
Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions.
Intervention:
See Contraindications, Warnings and Precautions  in prescribing information for clarithromycin.
 
See Drug Interactions in prescribing information for amoxicillin.
Tacrolimus
Clinical Impact:
Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.
Intervention:
Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact:
Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions (5.10), Clinical Pharmacology (12.2)].
Intervention:
Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
Interaction with Secretin Stimulation Test
Clinical Impact:
Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention:
Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology (12.2)].
False Positive Urine Tests for THC
Clinical Impact:
There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.
Intervention:
An alternative confirmatory method should be considered to verify positive results.
Other
Clinical Impact:
There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram).
Intervention:
Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole.


Table name:
Table 3Drugs that Can Increase the Risk of Bleeding
Drug  Class
Specific  Drugs
Anticoagulants 
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin 
Antiplatelet Agents 
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine 
Nonsteroidal Anti-Inflammatory Agents 
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac 
Serotonin Reuptake Inhibitors 
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone 


Table name:
Summary of AED interactions with topiramate (7.1).
AED Co-administered AED Concentration Topiramate Concentration
Phenytoin NC or 25% increasea 48% decrease
Carbamazepine (CBZ) NC 40% decrease
CBZ epoxideb NC NE
Valproic acid 11% decrease 14% decrease
Phenobarbital NC NE
Primidone NC NE
Lamotrigine NC at TPM doses up to 400mg/day 13% decrease


Table name:
Table 5: AED Drug Interactions with Oxcarbazepine
AED Coadministered
(daily dose)
IR-Oxcarbazepine
(daily dose)
Influence of IR-Oxcarbazepine on AED Concentration Mean Change [90% Confidence Interval] Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval) Recommendation
Carbamazepine
(400 – 2000 mg)
900 mg ncnc denotes a mean change of less than 10% 40% decrease
[CI: 17% decrease, 57% decrease]
Consider initiating Oxtellar XR® at a higher dose. Monitor and titrate dose to desired clinical effect (see 2.6)
Phenobarbital
(100 – 150 mg)
600 – 1800 mg 14% increase
[CI: 2% increase, 24% increase]
25% decrease
[CI: 12% decrease, 51% decrease]
Phenytoin
(250 – 500 mg)
600 – 1800
>1200-2400
nc , Pediatrics
up to 40% increaseMean increase in adults at high doses of immediate-release oxcarbazepine
[CI: 12% increase, 60% increase]
30% decrease
[CI: 3% decrease, 48% decrease]
Valproic Acid
(400 – 2800 mg)
600-1800 nc 18% decrease
[CI: 13% decrease, 40% decrease]
Monitor. Dose adjustment of Oxtellar XR® may not be needed.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Grapefruit juice Avoid grapefruit juice


Table name:
Table 2: Drug-Thyroidal Axis Interactions
   Drug or Drug Class    Effect
   Drugs that may reduce TSH secretion–the reduction is not sustained; therefore, hypothyroidism does not occur
  Dopamine / Dopamine Agonists Glucocorticoids Octreotide

  Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day).
   Drugs that alter thyroid hormone secretion
   Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
  Aminoglutethimide Amiodarone Iodide(including iodine-containing   Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide







  Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients.  The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T and T levels and increase TSH, although all values remain within normal limits in most patients. 4 3
   Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
  Amiodarone Iodide(including iodine-containing      Radiographic contrast agents)

  Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma).  Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
   Drugs that may decrease T 4 absorption, which may result in hypothyroidism
  Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate










  Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism.  Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents.  Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
   Drugs that may alter T 4 and T 3 serum transport  - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
   Drugs that may increase serum TBG concentration    Drugs that may decrease serum TBG concentration
  Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen





  Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid


   Drugs that may cause protein-binding site displacement
  Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)





  Administration of these agents with levothyroxine results in an initial transient increase in FT . Continued administration results in a decrease in serum T , and normal FT and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T and T to TBG and transthyretin. An initial increase in serum FT is followed by return of FT to normal levels with sustained therapeutic serum salicylate concentrations, although total-T levels may decrease by as much as 30%. 4 4 4 4 3 4 4 4
   Drugs that may alter T 4 and T 3 metabolism
   Drugs that may increase hepatic metabolism, which may result  in hypothyroidism
  Carbamazepine Hydantoins Phenobarbital Rifampin


  Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. 4
   Drugs that may decrease T 4 5’-deiodinase activity
  Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)




  Administration of these enzyme inhibitors decreases the peripheral conversion of T to T , leading to decreased T levels. However, serum T levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T and T   levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T concentrations by 30% with minimal change in serum T levels. However, long-term glucocorticoid therapy may result in slightly decreased T and T levels due to decreased TBG production (see above). 4 3 3 4 3 4 3 4 3 4
   Miscellaneous
  Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives

  Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
  Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors   (SSRIs; e.g., Sertraline)



  Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of  tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
  Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin




  Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
  Cardiac Glycosides   Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
  Cytokines - Interferon-α - Interleukin-2

  Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
  Growth Hormones - Somatrem - Somatropin

  Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
  Ketamine   Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
  Methylxanthine Bronchodilators - (e.g., Theophylline)
  Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
  Radiographic Agents   Thyroid hormones may reduce the uptake of I, I, and Tc. 123 131 99m
  Sympathomimetics   Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
  Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics









  These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.


Table name:
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
 Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)  Avoid atorvastatin
 HIV protease inhibitor (lopinavir plus ritonavir)  Use with caution and lowest dose necessary
 Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)  Do not exceed 20 mg atorvastatin daily
 HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
 Do not exceed 40 mg atorvastatin daily


Table name:
Table 3: Clinically Significant drug interactions with Celecoxib
Drugs  That  Interfere  with  Hemostasis
Clinical  Impact :
Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of Celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.
Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention :
Monitor patients with concomitant use of celecoxib capsules with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical  Impact :
Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)]. In two studies in healthy volunteers, and in patients with osteoarthritis and established heart disease respectively, celecoxib (200-400 mg daily) has demonstrated a lack of interference with the cardioprotective antiplatelet effect of aspirin (100-325 mg).
Intervention :
Concomitant use of celecoxib capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. Celecoxib capsules are not a substitute for low dose aspirin for cardiovascular protection.
ACE  Inhibitors Angiotensin  Receptor  Blockers and  Beta - Blockers
Clinical  Impact :
NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).
In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention :
During concomitant use of celecoxib capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of celecoxib capsules and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical  Impact :
Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention :
During concomitant use of celecoxib capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Digoxin
Clinical  Impact :
The concomitant use of Celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention :
During concomitant use of celecoxib capsules and digoxin, monitor serum digoxin levels.
Lithium
Clinical  Impact :
NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention :
During concomitant use of celecoxib capsules and lithium, monitor patients for signs of lithium toxicity. 
Methotrexate 
Clinical  Impact :
Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). 

Celecoxib has no effect on methotrexate pharmacokinetics. 
Intervention :
During concomitant use of celecoxib capsules and methotrexate, monitor patients for methotrexate toxicity. 
Cyclosporine 
Clinical  Impact :
Concomitant use of celecoxib capsules and cyclosporine may increase cyclosporine’s nephrotoxicity. 
Intervention :
During concomitant use of celecoxib capsules and cyclosporine, monitor patients for signs of worsening renal function. 
NSAIDs  and  Salicylates 
Clinical  Impact :
Concomitant use of Celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention :
The concomitant use of Celecoxib with other NSAIDs or salicylates is not recommended. 
Pemetrexed 
Clinical  Impact :
Concomitant use of celecoxib capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). 
Intervention :
During concomitant use of celecoxib capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. 

NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. 

In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. 
CYP2C9  Inhibitors  or  inducers 
Clinical  Impact :
Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Coadministration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of celecoxib. 
Intervention :
Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers. [see Clinical Pharmacology (12.3)].
CYP2D6  substrates 
Clinical  Impact :
In  vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is a potential for an in  vivo drug interaction with drugs that are metabolized by CYP2D6 (e.g. atomoxetine), and celecoxib may enhance the exposure and toxicity of these drugs. 
Intervention :
Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2D6 substrates. [see Clinical Pharmacology (12.3)].
Corticosteroids 
Clinical  Impact :
Concomitant use of corticosteroids with celecoxib capsules may increase the risk of GI ulceration or bleeding. 
Intervention :
Monitor patients with concomitant use of celecoxib capsules with corticosteroids for signs of bleeding [see Warnings and Precautions (5.2)].


Table name:
Drug Interactions Associated with Increased Risk of  Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice Avoid grapefruit juice


Table name:
Table 18Summary of Effect of Coadministered Drugs on Exposure to Active Moiety(Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients withSchizophrenia
*Change relative to reference
Coadministered Drug
Dosing Schedule

Effect on Active
Moiety
(Risperidone + 9-
Hydroxy-
Risperidone (Ratio*)

Risperidone Dose
Recommendation

Coadministered Drug
Risperidone
AUC
Cm a x

Enzyme (CYP2D6) 
Inhibitors 





Fluoxetine 
20 mg/day
2 or 3 mg twice
daily
1.4
1.5
Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine 
10 mg/day
4 mg/day
1.3
-
Re-evaluate dosing. 

20 mg/day
4 mg/day
1.6
-
Do not exceed 8 mg/day

40 mg/day
4 mg/day
1.8
-

Enzyme (CYP3A/ 
PgP inducers) 





Carbamazepine 
573 ± 168 mg/day
3 mg twice daily
0.51
0.55
Titrate dose upwards.
Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) 
Inhibitors 





Ranitidine 
150 mg twice daily
1 mg single dose
1.2
1.4
Dose adjustment not
needed
Cimetidine 
400 mg twice daily
1 mg single dose
1.1
1.3
Dose adjustment not
needed
Erythromycin 
500 mg four times
daily
1 mg single dose
1.1
0.94
Dose adjustment not
needed
Other Drugs 





Amitriptyline 
50 mg twice daily
3 mg twice daily
1.2
1.1
Dose adjustment not
needed


Table name: ContraindicatedAvoid UseUse with cautionUse with cautionUse with caution
Table 4: Drugs That are Affected by and Affecting CIPRO
Drugs That are Affected by CIPRO
Drug(s) Recommendation Comments
Tizanidine
 
Concomitant administration of tizanidine and CIPRO XR is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)].
Theophylline Avoid Use (Plasma Exposure Likely to be Increased and Prolonged) Concurrent administration of CIPRO XR with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions (5.9)].
Drugs Known to Prolong QT Interval
 
Cipro XR may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.11) and Use in Specific Populations (8.5)].
Oral antidiabetic drugs Use with caution Glucose-lowering effect potentiated Hypoglycemia sometimes severe has been reported when CIPRO XR and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when CIPRO XR is co-administered with oral antidiabetic drugs [see Adverse Reactions (6.1)].
Phenytoin Use with caution Altered serum levels of phenytoin (increased and decreased) To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon CIPRO XR discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of CIPRO XR with phenytoin.
Cyclosporine Use with caution (transient elevations in serum creatinine) Monitor renal function (in particular serum creatinine) when CIPRO XR is co-administered with cyclosporine.
Anti-coagulant drugs Use with caution (Increase in anticoagulant effect) The risk may vary with the underlying infection, age and general status of the patient so that the contribution of CIPRO XR to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of CIPRO XR with an oral anti-coagulant (for example, warfarin).
Methotrexate Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant CIPRO XR therapy is indicated.
Ropinirole
 
Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with CIPRO XR [see Warnings and Precautions (5.15)].
Clozapine
 
Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with CIPRO XR are advised.
NSAIDs
 
Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil Use with caution Two-fold increase in exposure Monitor for sildenafil toxicity [see Clinical Pharmacology (12.3)]..
Duloxetine Avoid Use Five-fold increase in duloxetine exposure If unavoidable monitor, for duloxetine toxicity
Caffeine/Xanthine Derivatives Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life CIPRO XR inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of CIPRO XR
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products) CIPRO XR should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration ( 2)]. Decrease CIPRO XR absorption, resulting in lower serum and urine levels considerably lower than desired for concurrent administration of these agents with CIPRO XR
Probenecid Use with caution (interferes with renal tubular secretion of CIPRO XR and increases CIPRO XR serum levels) Potentiation of CIPRO XR toxicity may occur.


Table name:
Table 9: Drugs That are Affected by and Affecting Ciprofloxacin Tablets
Drugs That are Affected by C iprofloxacin   Tablets
Drug(s) Recommendation Comments
Tizanidine Contraindicated Concomitant administration of tizanidine and ciprofloxacin tablets is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [ see Contraindications ( 4.2 )]
Theophylline Avoid Use (Plasma Exposure Likely to be Increased and Prolonged) Concurrent administration of ciprofloxacin tablets with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [s ee Warnings and Precautions ( 5.9 ) ] .
Drugs Known to Prolong QT Interval Avoid Use Ciprofloxacin tablets may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions ( 5.11 )   and Use in
Specific Populations ( 8.5 )].
Oral antidiabetic drugs Use with caution Glucose-lowering effect potentiated
Hypoglycemia sometimes severe has been reported when ciprofloxacin tablets and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin tablets is co-administered with oral antidiabetic drugs [see Adverse Reactions ( 6.1)].
Phenytoin Use with caution Altered serum levels of phenytoin (increased and decreased) To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin tablets discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin tablets with phenytoin.
Cyclosporine Use with caution (transient elevations in serum creatinine) Monitor renal function (in particular serum creatinine) when ciprofloxacin tablets is co-administered with cyclosporine.
Anti-coagulant drugs Use with caution (Increase in anticoagulant effect) The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin tablets to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin tablets with an oral anti-coagulant (for example, warfarin).
Methotrexate Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin tablets therapy is indicated.
Ropinirole Use with caution Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin tablets [ see Warnings and Precautions ( 5.16 ) ] .
Clozapine Use with caution Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin tablets are advised.
NSAIDs Use with caution Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil Use with caution Two-fold increase in exposure Monitor for sildenafil toxicity [see  clinical  Pharmacology ( 12.3)].
Duloxetine Avoid Use
Five-fold increase in duloxetine exposure
If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life Ciprofloxacin tablets inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin Tablets
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx®
(didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)
Ciprofloxacin tablets should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration  ( 2.4 ) ] .








Decrease ciprofloxacin tablets absorption, resulting in lower serum and urine levels
Probenecid
Use with caution (interferes with renal tubular secretion of ciprofloxacin tablets and increases ciprofloxacin tablets serum levels)
Potentiation of ciprofloxacin tablets toxicity may occur.


Table name:
Table II. Clinically significant drug interactions with theophylline.
Drug Type of Interaction Effect
Adenosine Theophylline blocks adenosine receptors. Higher doses of adenosine may be required to achieve desired effect.
Alcohol A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours. 30% increase
Allopurinol Decreases theophylline clearance at allopurinol doses ≥600 mg/day. 25% increase
Aminoglutethimide Increases theophylline clearance by induction of microsomal enzyme activity. 25% decrease
Carbamazepine Similar to aminoglutethimide. 30% decrease
Cimetidine Decreases theophylline clearance by inhibiting cytochrome P450 1A2. 70% increase
Ciprofloxacin Similar to cimetidine. 40% increase
Clarithromycin Similar to erythromycin. 25% increase
Diazepam Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram Decreases theophylline clearance by inhibiting hydroxylation and demethylation. 50% increase
Enoxacin Similar to cimetidine. 300% increase
Ephedrine Synergistic CNS effects Increased frequency of nausea, nervousness, and insomnia.
Erythromycin Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3. 35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown. 30% increase
Flurazepam Similar to diazepam. Similar to diazepam.
Fluvoxamine Similar to cimetidine. Similar to cimetidine.
Halothane Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines. Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-A Decreases theophylline clearance. 100% increase
Isoproterenol (IV) Increase theophylline clearance. 20% increase
Ketamine Pharmacologic May lower theophylline seizure threshold.
Lithium Theophylline increases renal lithium clearance. Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam Similar to diazepam. Similar to diazepam.
Methotrexate (MTX) Decreases theophylline clearance. 20% increase after low dose MTX, higher dose MTX may have a greater effect.
Mexiletine Similar to disulfiram. 80% increase
Midazolam Similar to diazepam. Similar to diazepam.
Moricizine Increases theophylline clearance. 25% decrease
Pancuronium Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition. Larger dose of pancuronium may be required to achieve neuromuscular blockade.
Pentoxifylline Decreases theophylline clearance. 30% increase
Phenobarbital (PB) Similar to aminoglutethimide. 25% decrease after two weeks of concurrent PB.
Phenytoin Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption. Serum theophylline and phenytoin concentrations decrease about 40%.
Propafenone Decreases theophylline clearance and pharmacologic interaction. 40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Propranolol Similar to cimetidine and pharmacologic interaction. 100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Rifampin Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity. 20 to 40% decrease
Sulfinpyrazone Increase theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline. 20% increase
Tacrine Similar to cimetidine, also increases renal clearance of theophylline. 90% increase
Thiabendazole Decreases theophylline clearance. 190% increase
Ticlopidine Decreases theophylline clearance. 60% increase
Troleandomycin Similar to erythromycin. 33 to 100% increase depending on troleandomycin dose.
Verapamil Similar to disulfiram. 20% increase


Table name:
Drugs that Affect Renal Function A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDS], COX-2 inhibitors may impair the excretion of digoxin.
Antiarrthymics Dofetilide Concomitant administration with digoxin was associated with a higher rate of torsades de pointes
Sotalol Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
Dronedarone Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone Analog Teriparatide Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement Thyroid Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics Epinephrine
Norepinephrine     
Dopamine
Can increase the risk of cardiac arrhythmias
Neuromuscular Blocking Agents      Succinylcholine May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.
Supplements Calcium If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.
Hyperpolarization-activated cyclic nucleotide-gated channel blocker Ivabradine Can increase the risk of bradycardia


Table name:
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
↓= Decreased (induces lamotrigine glucuronidation).
↑= Increased (inhibits lamotrigine glucuronidation).
?= Conflicting data.
Concomitant  Drug
Effect  on  Concentration  of  Lamotrigine  or  Concomitant  Drug
Clinical  Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 
150 mcg levonorgestrel 
↓ lamotrigine 
↓ levonorgestrel 
Decreased lamotrigine concentrations approximately 50%. 
Decrease in levonorgestrel component by 19%. 
Carbamazepine and carbamazepine epoxide 
↓ lamotrigine 
? carbamazepine epoxide 
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. 
May increase carbamazepine epoxide levels. 
Lopinavir/ritonavir
↓ lamotrigine 

Decreased lamotrigine concentration approximately 50%. 

Atazanavir/ritonavir
↓ lamotrigine 

Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone
↓ lamotrigine
Decreased lamotrigine concentration approximately 40%.
Phenytoin
↓ lamotrigine
Decreased lamotrigine concentration approximately 40%.
Rifampin
↓ lamotrigine
Decreased lamotrigine AUC approximately 40%.
Valproate
↑ lamotrigine  
? valproate




Increased lamotrigine concentrations slightly more than 2-fold. 
There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.


Table name:
Table 1: Clinically Significant Drug Interactions with Naproxen
Drugs That Interfere with Hemostasis
Clinical Impact: Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of naproxen tablets with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: Concomitant use of naproxen tablets and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen tablets are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: During concomitant use of naproxen tablets and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of naproxen tablets and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention During concomitant use of naproxen tablets with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact: The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of naproxen tablets and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen tablets and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of naproxen tablets and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of naproxen tablets and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of naproxen tablets and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of naproxen tablets and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of naproxen tablets and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact: Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention: Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen tablets are not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen tablets are not recommended.
Cholestyramine
Clinical Impact: Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention: Concomitant administration of cholestyramine with naproxen tablets are not recommended.
Probenecid
Clinical Impact: Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention: Patients simultaneously receiving naproxen tablets and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact: Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention: Patients simultaneously receiving naproxen tablets and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.


Table name:
 Diuretics
 Clinical Impact: Diuretic-induced sodium loss may reduce lithium clearance and increase serum lithium concentrations. 
 Intervention:  More frequent monitoring of serum electrolyte and lithium concentrations. Reduce lithium dosage based on serum lithium concentration and clinical response [see Dosage and Administration (2.6), Warning and Precautions (5.3)].
 Examples:  hydrochlorothiazide, chlorothiazide, furosemide
 Non-Steroidal Anti-inflammatory Drugs (NSAID)
 Clinical Impact:  NSAID decrease renal blood flow, resulting in decreased renal clearance and increased serum lithium concentrations.
 Intervention:  More frequent serum lithium concentration monitoring. Reduce lithium dosage based on serum lithium concentration and clinical response [see Dosage and Administration (2.6)].
 Examples:  indomethacin, ibuprofen, naproxen
 Renin-Angiotensin System Antagonists
 Clinical Impact:  Concomitant use increase steady-state serum lithium concentrations.
 Intervention:  More frequent monitoring of serum lithium concentration. Reduce lithium dosage based on serum lithium concentration and clinical response [see Dosage and Administration (2.6)].
 Examples:  lisinopril, enalapril, captopril, valsartan
 Serotonergic Drugs
 Clinical Impact:  Concomitant use can precipitate serotonin syndrome.
 Intervention:  Monitor patients for signs and symptoms of serotonin syndrome, particularly during lithium initiation. If serotonin syndrome occurs, consider discontinuation of lithium and/or concomitant serotonergic drugs [see Warnings and Precautions (5.6)].
 Examples:  selective serotonin reuptake inhibitors (SSRI), serotonin and norepinephrine reuptake inhibitors (SNRI), monoamine oxidase inhibitors (MAOI)
 Nitroimidazole Antibiotics
 Clinical Impact:  Concomitant use may cause lithium toxicity due to reduced renal clearance.
 Intervention:  More frequent monitoring of serum lithium concentration. Reduce lithium dosage based on serum lithium concentration and clinical response [see Dosage and Administration (2.6)].
 Examples:  metronidazole
 Acetazolamide, Urea, Xanthine Preparations, Alkalinizing Agents
 Clinical Impact:  Concomitant use can lower serum lithium concentrations by increasing urinary lithium excretion.
 Intervention:  More frequent serum lithium concentration monitoring. Increase lithium dosage based on serum lithium concentration and clinical response [see Dosage and Administration (2.6)].
 Examples:  acetazolamide, theophylline, sodium bicarbonate
 Methyldopa, Phenytoin and Carbamazepine
 Clinical Impact:  Concomitant use may increase risk of toxic effects of these drugs
 Intervention:  Monitor patients closely for symptoms of toxicity of methyldopa, phenytoin, and carbamazepine.
 Iodide Preparations
 Clinical Impact:  Concomitant use may produce hypothyroidism.
 Intervention:  Monitor patients for signs or symptoms of hypothyroidism [see Warnings and Precautions (5.7)].
 Examples:  potassium iodide
 Calcium Channel Blocking Agents (CCB)
 Clinical Impact:  Concomitant use may increase the risk of neurologic adverse reactions in the form of ataxia, tremors, nausea, vomiting, diarrhea and/or tinnitus.
 Intervention:  Monitor for neurologic adverse reactions.
 Examples:  diltiazem, nifedipine, verapamil
 Atypical and Typical Antipsychotic Drugs
 Clinical Impact:  Reports of neurotoxic reactions in patients treated with both lithium and an antipsychotic, ranging from extrapyramidal symptoms to neuroleptic malignant syndrome, as well as reports of an encephalopathic syndrome in few patients treated with concomitant therapy [see Warnings and Precautions (5.5)].
 Intervention:  Monitor for neurologic adverse reactions.
 Examples:  risperidone, haloperidol, thioridazine, fluphenazine, chlorpromazine, perphenazine, clozapine
 Neuromuscular Blocking Agents
 Clinical Impact:  Lithium may prolong the effects of neuromuscular blocking agents.
 Intervention:  Monitor for prolonged paralysis or toxicity.
 Examples:  succinylcholine, pancuronium


Table name:
Table 2: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 5 mg in BPH patients on stable alpha-blocker therapy (Study 1)
Alpha-Blocker Simultaneous dosing of Vardenafil 5 mg
and Alpha-Blocker,
Placebo-Subtracted
Dosing of Vardenafil 5 mg
and Alpha-Blocker
Separated by 6 Hours,
Placebo-Subtracted
Terazosin
5 or 10 mg daily
Standing SBP -3 (-6.7, 0.1) -4 (-7.4, -0.5)
Supine SBP -4 (-6.7, -0.5) -4 (-7.1, -0.7)
Tamsulosin
0.4 mg daily
Standing SBP
Supine SBP
-6 (-9.9, -2.1)
-4 (-7.0, -0.8)
-4 (-8.3, -0.5)
-5 (-7.9, -1.7)


Table name:
 Drug Interactions Associated with Increased
Risk of Myopathy/Rhabdomyolysis (2.3, 2.4, 4, 5.1, 7.1, 7.2,
7.3, 7.8, 12.3)
 Interacting Agents  Prescribing
   Recommendations
 Strong CYP3A4 Inhibitors, (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat­containing products), gemfibrozil, cyclosporine, danazol  Contraindicated with ezetimibe and simvastatin
   
 Verapamil, diltiazem, dronedarone  Do not exceed 10 mg/10 mg ezetimibe and simvastatin daily
 Amiodarone, amlodipine, ranolazine  Do not exceed 10 mg/20 mg ezetimibe and simvastatin daily
 Lomitapide  For patients with HoFH, do not exceed 10 mg/20 mg ezetimibe and simvastatin daily*
 Grapefruit juice  Avoid grapefruit juice
 * For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 10 mg/40 mg ezetimibe and simvastatin when taking lomitapide.


Table name:
Table 7 Summary of AED Interactions with Oxcarbazepine
AED Coadministered Dose of AED (mg/day) Oxcarbazepine dose (mg/day) Influence of Oxcarbazepine on AED Concentration (Mean change, 90% Confidence Interval) Influence of AED on MHD Concentration (Mean change, 90% Confidence Interval)
Carbamazepine 400 to 2000 900 ncnc denotes a mean change of less than 10% 40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital 100 to 150 600 to 1800 14% increase [CI: 2% increase, 24% increase] 25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin 250 to 500 600 to 1800 >1200 to 2400 nc, Pediatrics up to 40% increaseMean increase in adults at high oxcarbazepine doses [CI: 12% increase, 60% increase] 30% decrease [CI: 3% decrease, 48% decease]
Valproic acid 400 to 2800 600 to 1800 nc 18% decrease [CI: 13% decrease, 40% decrease]


Table name:
Drugs That Interfere with Hemostasis
Clinical Impact: • Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone.
• Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of naproxen delayed-release tablets with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding ( see WARNINGS; Hematologic Toxicity ).
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation) .
Intervention: Concomitant use of naproxen delayed-release tablets and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity).
Naproxen delayed-release tablets are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).
• In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: • During concomitant use of naproxen delayed-release tablets and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.
• During concomitant use of naproxen delayed-release tablets and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia).
When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention During concomitant use of naproxen delayed-release tablets with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact: The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of naproxen delayed-release tablets and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance . The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen delayed-release tablets and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of naproxen delayed-release tablets and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of naproxen delayed-release tablets and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of naproxen delayed-release tablets and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of naproxen delayed-release tablets and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of naproxen delayed-release tablets and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.

NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.

In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact: Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention: Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen delayed-release tablets is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed-release tablets is not recommended.
Cholestyramine
Clinical Impact: Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention: Concomitant administration of cholestyramine with naproxen delayed-release tablets is not recommended.
Probenecid
Clinical Impact: Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention: Patients simultaneously receiving naproxen delayed-release tablets and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact: Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin .
Intervention: Patients simultaneously receiving naproxen delayed-release tablets and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.


Table name:
Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s)
Recommendation
Comments
Tizanidine
Contraindicated
Concomitant administration of tizanidine and ciprofloxacin  is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2) ].
Theophylline
Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)
Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate. [See Warnings and Precautions (5.6) .]
Drugs Known to Prolong QT Interval
Avoid Use

Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see  Warnings and Precautions (5.10) and Use in Specific Populations (8.5) ].
Oral antidiabetic drugs
Use with caution Glucose-lowering effect potentiated
Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs. [See Adverse Reactions (6.1) .]
Phenytoin
Use with caution Altered serum levels of phenytoin
(increased and decreased)

To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin with phenytoin.
Cyclosporine
Use with caution (transient elevations in serum creatinine)
Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs
Use with caution (Increase in anticoagulant effect)
The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate
Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels
Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole
Use with caution
Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin [see Warnings and Precautions (5.15) ].
Clozapine
Use with caution
Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs
Use with caution
Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies in and postmarketing.
Sildenafil
Use with caution Two-fold increase in exposure
Monitor for sildenafil toxicity (see Pharmacokinetics 12.3 ).
Duloxetine
Avoid Use
Five-fold increase in duloxetine exposure
If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives
Use with caution Reduced clearance resulting in elevated levels and prolongation
of serum half-life
Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx® (didanosine) chewable/ buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)
Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2) ].
Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid
Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)
Potentiation of ciprofloxacin toxicity may occur.


Table name:
Table 18. Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug Dosing Schedule Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio Change relative to reference ) Risperidone Dose Recommendation
Coadministered Drug Risperidone AUC Cmax
Enzyme (CYP2D6) Inhibitors
Fluoxetine 20 mg/day 2 mg or
3 mg twice daily
1.4 1.5 Reevaluate dosing. Do not exceed 8 mg/day
Paroxetine 10 mg/day 4 mg/day 1.3 -- Reevaluate dosing. Do not exceed 8 mg/day
20 mg/day 4 mg/day 1.6 --
40 mg/day - 4 mg/day 1.8 --
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine 573 ± 168 mg/day 3 mg twice daily 0.51 0.55 Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine 150 mg twice daily 1 mg single dose 1.2 1.4 Dose adjustment not needed
Cimetidine 400 mg twice daily 1 mg single dose 1.1 1.3 Dose adjustment not needed
Erythromycin 500 mg four times daily 1 mg single dose 1.1 0.94 Dose adjustment not needed
Other Drugs
Amitriptyline 50 mg twice daily 3 mg twice daily 1.2 1.1 Dose adjustment not needed


Table name:
DRUG DESCRIPTION OF INTERACTION
Corticosteroids Decreases plasma salicylate level; tapering doses of steroids may promote salicylism.
Acidifying Agents Increases plasma salicylate level.
Alkanizing Agents Decreased plasma salicylate levels.


Table name:
 
Interacting Drug
 

 
Interaction
 

 
Multivalent cation-containing products including antacids, metal cations or didanosine
 

Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products.  Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)

 
Warfarin
 

Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)

 
Anti-diabetic agents
 

Carefully monitor blood glucose (5.11, 7.3)



Table name:
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Do not exceed 40 mg atorvastatin daily


Table name:
Table 9: Drugs That are Affected by and Affecting Ciprofloxacin Tablets
Drugs That are Affected by C iprofloxacin   Tablets
Drug(s) Recommendation Comments
Tizanidine Contraindicated Concomitant administration of tizanidine and ciprofloxacin tablets is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [ see Contraindications ( 4.2 )]
Theophylline Avoid Use (Plasma Exposure Likely to be Increased and Prolonged) Concurrent administration of ciprofloxacin tablets with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [s ee Warnings and Precautions ( 5.9 ) ] .
Drugs Known to Prolong QT Interval Avoid Use Ciprofloxacin tablets may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions ( 5.11 )   and Use in
Specific Populations ( 8.5 )].
Oral antidiabetic drugs Use with caution Glucose-lowering effect potentiated
Hypoglycemia sometimes severe has been reported when ciprofloxacin tablets and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin tablets is co-administered with oral antidiabetic drugs [see Adverse Reactions ( 6.1)].
Phenytoin Use with caution Altered serum levels of phenytoin (increased and decreased) To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin tablets discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin tablets with phenytoin.
Cyclosporine Use with caution (transient elevations in serum creatinine) Monitor renal function (in particular serum creatinine) when ciprofloxacin tablets is co-administered with cyclosporine.
Anti-coagulant drugs Use with caution (Increase in anticoagulant effect) The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin tablets to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin tablets with an oral anti-coagulant (for example, warfarin).
Methotrexate Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin tablets therapy is indicated.
Ropinirole Use with caution Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin tablets [ see Warnings and Precautions ( 5.16 ) ] .
Clozapine Use with caution Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin tablets are advised.
NSAIDs Use with caution Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil Use with caution Two-fold increase in exposure Monitor for sildenafil toxicity [see  clinical  Pharmacology ( 12.3)].
Duloxetine Avoid Use
Five-fold increase in duloxetine exposure
If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life Ciprofloxacin tablets inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin Tablets
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx®
(didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)
Ciprofloxacin tablets should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration  ( 2.4 ) ] .








Decrease ciprofloxacin tablets absorption, resulting in lower serum and urine levels
Probenecid
Use with caution (interferes with renal tubular secretion of ciprofloxacin tablets and increases ciprofloxacin tablets serum levels)
Potentiation of ciprofloxacin tablets toxicity may occur.


Table name:
Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
 Coadministered Drug
 Dosing Schedule
 Effect on Active
Moiety (Risperidone + 9-
Hydroxy- Risperidone (Ratio*)
 Risperidone Dose
Recommendation
 
 Coadministered Drug
 Risperidone
 AUC
 Cmax
 
 Enzyme (CYP2D6)
Inhibitors
 
 
 
 
 
 Fluoxetine
 20 mg/day 
 2 or 3 mg twice
daily
 1.4 
 1.5
 Re-evaluate dosing. Do not exceed 8 mg/day
 Paroxetine
 10 mg/day 
 4 mg/day
 1.3
 -
 Re-evaluate dosing. 
 
 20 mg/day 
 4 mg/day
 1.6
 -
 Do not exceed 8 mg/day
 
 40 mg/day 
 4 mg/day
 1.8
 -
 
 Enzyme (CYP3A/ PgP inducers) Inducers
 
 
 
 
 
 Carbamazepine 
 573 ± 168 mg/day
 3 mg twice daily
 0.51 
 0.55
 Titrate dose upwards.
Do not exceed twice the patient’s usual dose
 Enzyme (CYP3A)
Inhibitors
 
 
 
 
 
 Ranitidine 
 150 mg twice daily
 1 mg single dose
 1.2 
 1.4
 Dose adjustment not
needed
 Cimetidine 
 400 mg twice daily
 1 mg single dose
 1.1 
 1.3
 Dose adjustment not
needed
 Erythromycin 

 500 mg four times
daily
 1 mg single dose
 1.1 
 0.94
 Dose adjustment not
needed
 
 
 
 
 
 
 Other Drugs
 
 
 
 
 
 Amitriptyline 
 50 mg twice daily
 3 mg twice daily
 1.2 
 1.1
 Dose adjustment not
needed


Table name:
May Require a Decrease in Dose at Cessation of Smoking Possible Mechanism
Acetaminophen, caffeine, imipramine, oxazepam, pentazocine, propranolol, or other beta-blockers, theophylline Deinduction of hepatic enzymes on smoking cessation.
Insulin Increase of subcutaneous insulin absorption with smoking cessation.
Adrenergic antagonists (e.g. prazosin, labetalol) Decrease in circulating catecholamines with smoking cessation.
May Require an Increase in Dose at Cessation of Smoking Possible Mechanism
Adrenergic agonists (e.g. isoproterenol, phenylephrine) Decrease in circulating catecholamines with smoking cessation.


Table name:
Interacting Drug
Interaction
Multivalent cation-containing
products including antacids,
metal cations or didanosine
Absorption of levofloxacin is decreased
when the tablet formulation is taken within
2 hours of these products. ( 2.4, 7.1)
Warfarin
Effect may be enhanced. Monitor
prothrombin time, INR, watch for bleeding
( 7.2)
Antidibetic agents
Carefully monitor blood glucose ( 5.12, 7.3)


Table name:
Table 3 Clinically Significant Drug Interactions with Meloxicam
Drugs  that  Interfere  with  Hemostasis 
Clinical  Impact
Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. 
Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. 
Intervention

Monitor patients with concomitant use of Meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin 
Clinical  Impact
Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].
Intervention

Concomitant use of Meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. Meloxicam is not a substitute for low dose aspirin for cardiovascular protection.
ACE  Inhibitors Angiotensin  Receptor  Blockers or  Beta - Blockers 
Clinical  Impact
NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). 
In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, coadministration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. 
Intervention

During concomitant use of Meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.  During concomitant use of Meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics 
Clinical  Impact
Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. 
Intervention

During concomitant use of Meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Lithium 
Clinical  Impact
NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [see Clinical Pharmacology (12.3)].
Intervention

During concomitant use of Meloxicam and lithium, monitor patients for signs of lithium toxicity. 
Methotrexate 
Clinical  Impact
Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). 
Intervention

During concomitant use of Meloxicam and methotrexate, monitor patients for methotrexate toxicity. 
Cyclosporine 
Clinical  Impact
Concomitant use of Meloxicam and cyclosporine may increase cyclosporine's nephrotoxicity. 
Intervention

During concomitant use of Meloxicam and cyclosporine, monitor patients for signs of worsening renal function. 
NSAIDs  and  Salicylates 
Clinical  Impact
Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention

The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended. 
Pemetrexed 
Clinical  Impact
Concomitant use of Meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). 
Intervention

During concomitant use of Meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. 

Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. 

In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended. 


Table name:
Table 4: Clinically Important Drug Interactions with VIIBRYD
Concomitant Drug Name or Drug Class Clinical Rationale Clinical Recommendation
Monoamine Oxidase Inhibitors (MAOIs) The concomitant use of MAOIs and serotonergic drugs including VIIBRYD increases the risk of serotonin syndrome. VIIBRYD is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [see Contraindications (4), Dosage and Administration (2.3), and Warnings and Precautions (5.2)].
Other Serotonergic Drugs The concomitant use of serotonergic drugs including VIIBRYD and other serotonergic drugs increases the risk of serotonin syndrome. Monitor patients for signs and symptoms of serotonin syndrome, particularly during VIIBRYD initiation. If serotonin syndrome occurs, consider discontinuation of VIIBRYD and/or concomitant serotonergic drugs [see Warnings and Precautions (5.2)].
Antiplatelet Agents and Anticoagulants Serotonin release by platelets plays an important role in hemostasis. The concurrent use of an antiplatelet agent or anticoagulant with VIIBRYD may potentiate the risk of bleeding. Inform patients of the increased risk of bleeding with the concomitant use of VIIBRYD and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio (INR) when initiating or discontinuing VIIBRYD [see Warnings and Precautions (5.3)].
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin, voriconazole) The concomitant use of VIIBRYD and strong CYP3A4 inhibitors increased the exposure of vilazodone compared to the use of VIIBRYD alone [see Clinical Pharmacology (12.3)]. The VIIBRYD dose should not exceed 20 mg once daily with the concomitant use of a strong CYP3A4 inhibitor [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].
Strong CYP3A4 Inducers (e.g.,
carbamazepine, phenytoin, rifampin)
The concomitant use of VIIBRYD and strong CYP3A4 inducers decreased the exposure of vilazodone compared to the use of VIIBRYD alone [see Clinical Pharmacology (12.3)]. Based on clinical response, consider increasing the dosage of VIIBRYD, over 1 to 2 weeks in patients taking strong CYP3A4 inducers for greater than 14 days [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].
Digoxin Digoxin is a narrow therapeutic index drug. Concomitant use of VIIBRYD increased digoxin concentrations [see Clinical Pharmacology (12.3)]. Measure serum digoxin concentrations before initiating concomitant use of VIIBRYD. Continue monitoring and reduce digoxin dose as necessary.


Table name:
Interacting  Drug
Interaction
Multivalent cation-containing products including: antacids, sucralfate, multivitamins
Decreased moxifloxacin absorption. Take moxifloxacin hydrochloride tablet at least 4 hours before or 8 hours after these products. (2.2, 7.1, 12.3)
Warfarin
Anticoagulant effect enhanced. Monitor prothrombin time/INR, and bleeding. (6, 7.2, 12.3)
Class IA and Class III antiarrhythmics:
Proarrhythmic effect may be enhanced. Avoid concomitant use. (5.6, 7.5)
Antidiabetic agents
Carefully monitor blood glucose. (5.11, 7.3)


Table name:
NA – Not available/reported
Digoxin concentrations increased greater than 50%
   Digoxin Serum   
Concentration Increase
   Digoxin AUC   
Increase
Recommendations
Amiodarone 70% NA Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring.
Captopril 58% 39%
Clarithromycin NA 70%
Dronedarone NA 150%
Gentamicin 129-212% NA
Erythromycin 100% NA
Itraconazole 80% NA
Lapatinib NA 180%
Nitrendipine 57% 15%
Propafenone NA 60-270%
Quinidine 100% NA
Ranolazine 50% NA
Ritonavir NA 86%
Telaprevir 50% 85%
Tetracycline 100% NA
Verapamil 50-75% NA
Digoxin concentrations increased less than 50%
Atorvastatin 22% 15% Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring.
Carvedilol 16% 14%
Conivaptan 33% 43%
Diltiazem 20% NA
Indomethacin 40% NA
Nefazodone 27% 15%
Nifedipine 45% NA
Propantheline 24% 24%
Quinine NA 33%
Rabeprazole 29% 19%
Saquinavir 27% 49%
Spironolactone      25% NA
Telmisartan 20-49% NA
Ticagrelor 31% 28%
Tolvaptan 30% 20%
Trimethoprim 22-28% NA
Digoxin concentrations increased, but magnitude is unclear
Alprazolam, azithromycin, cyclosporine, diclofenac, diphenoxylate, epoprostenol, esomeprazole, ibuprofen, ketoconazole, lansoprazole, metformin, omeprazole Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin concentrations decreased
Acarbose, activated charcoal, albuterol, antacids, certain cancer chemotherapy or radiation therapy, cholestyramine, colestipol, extenatide, kaolin-pectin, meals high in bran, metoclopramide, miglitol, neomycin, penicillamine, phenytoin, rifampin, St. John’s Wort, sucralfate, sulfasalazine Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20-40% as necessary.


Table name: Disopyramide Quinidine Dofetilide Amiodarone Sotalol Procainamide Digoxin Warfarin Carbamazepine Itraconazole Fluconazole Colchicine
(In Patients with Renal or Hepatic Impairment) Colchicine
(In Patients with Normal Renal and Hepatic Function) Pimozide Quetiapine Tolterodine
(Patients Deficient in CYP2D6 Activity) Atazanavir Saquinavir
(In Patients with
Decreased Renal Function) Ritonavir Etravirine Maraviroc Boceprevir
(In Patients with
Normal Renal Function) DidanosineZidovudine Verapamil Amlodipine Diltiazem Nifedipine Ergotamine Dihydroergotamine Cisapride Lovastatin Simvastatin Atorvastatin Pravastatin Fluvastatin Nateglinide Pioglitazone Repaglinide Rosiglitazone Insulin Cyclosporine Tacrolimus Sildenafil Tadalafil Vardenafil Omeprazole Theophylline Midazolam Alprazolam Triazolam Temazepam Nitrazepam Lorazepam Rifabutin Alfentanil Bromocriptine Cilostazol Methylprednisole Vinblastine Phenobarbital St. John’s Wort Hexobarbital Phenytoin Valproate Itraconazole Atazanavir Ritonavir (In Patients with
Decreased Renal Function) Saquinavir
(In Patients with
Decreased Renal Function) Etravirine Saquinavir
(In Patients with
Normal Renal Function) Ritonavir
(In Patients with
Normal Renal Function) Omeprazole Efavirenz Nevirapine Rifampicin Rifabutin Rifapentine
Table 8: Clinically Significant Drug Interactions with Clarithromycin
Drugs That Are Affected By Clarithromycin
Drug(s) with Pharmacokinetics Affected by Clarithromycin Recommendation Comments
Antiarrhythmics:
           
Not Recommended Disopyramide, Quinidine: There have been postmarketing reports of torsades de pointes occurring with concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QTc prolongation during co-administration of clarithromycin with these drugs [see Warnings and Precautions (5.3) ]. Serum concentrations of these medications should also be monitored. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with disopyramide and quinidine. There have been postmarketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide. Therefore, blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide.
 
Use With Caution Digoxin: Digoxin is a substrate for P-glycoprotein (Pgp) and clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are co-administered, inhibition of Pgp by clarithromycin may lead to increased exposure of digoxin. Elevated digoxin serum concentrations in patients receiving clarithromycin and digoxin concomitantly have been reported in postmarketing surveillance. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Monitoring of serum digoxin concentrations should be considered, especially for patients with digoxin concentrations in the upper therapeutic range.
Oral Anticoagulants:
 
Use With Caution Oral Anticoagulants: Spontaneous reports in the postmarketing period suggest that concomitant administration of clarithromycin and oral anticoagulants may potentiate the effects of the oral anticoagulants. Prothrombin times should be carefully monitored while patients are receiving clarithromycin and oral anticoagulants simultaneously [see Warnings and Precautions (5.4) ].
Antiepileptics:
 
Use With Caution Carbamazepine: Concomitant administration of single doses of clarithromycin and carbamazepine has been shown to result in increased plasma concentrations of carbamazepine. Blood level monitoring of carbamazepine may be considered. Increased serum concentrations of carbamazepine were observed in clinical trials with clarithromycin. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with carbamazepine.
Antifungals:
 
Use With Caution Itraconazole: Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when administered concomitantly (see also Itraconazole under “Drugs That Affect Clarithromycin” in the table below). Clarithromycin may increase the plasma concentrations of itraconazole. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions.
 
No Dose Adjustment Fluconazole: [see Pharmacokinetics (12.3) ]
Anti-Gout Agents:
 
Contraindicated Colchicine: Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. The dose of colchicine should be reduced when co-administered with clarithromycin in patients with normal renal and hepatic function [see Contraindications (4.4) and Warnings and Precautions (5.4) ].
 
Use With Caution
Antipsychotics:
 
Contraindicated Pimozide: [see Contraindications (4.2) ]
 
Quetiapine: Quetiapine is a substrate for CYP3A4, which is inhibited by clarithromycin. Co-administration with clarithromycin could result in increased quetiapine exposure and possible quetiapine related toxicities. There have been postmarketing reports of somnolence, orthostatic hypotension, altered state of consciousness, neuroleptic malignant syndrome, and QT prolongation during concomitant administration. Refer to quetiapine prescribing information for recommendations on dose reduction if co-administered with CYP3A4 inhibitors such as clarithromycin.
Antispasmodics:
 
Use With Caution Tolterodine: The primary route of metabolism for tolterodine is via CYP2D6. However, in a subset of the population devoid of CYP2D6, the identified pathway of metabolism is via CYP3A. In this population subset, inhibition of CYP3A results in significantly higher serum concentrations of tolterodine. Tolterodine 1 mg twice daily is recommended in patients deficient in CYP2D6 activity (poor metabolizers) when co-administered with clarithromycin.
Antivirals:
 
Use With Caution Atazanavir: Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction (see Atazanavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3) ].
 
Saquinavir: Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A and there is evidence of a bi-directional drug interaction (see Saquinavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3) ].
   
Ritonavir, Etravirine: (see Ritonavir and Etravirine under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3) ].
 
Maraviroc: Clarithromycin may result in increases in maraviroc exposures by inhibition of CYP3A metabolism. See Selzentry® prescribing information for dose recommendation when given with strong CYP3A inhibitors such as clarithromycin.
 
No Dose Adjustment Boceprevir: Both clarithromycin and boceprevir are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when co-administered. No dose adjustments are necessary for patients with normal renal function (see Victrelis® prescribing information).
 
 
Zidovudine: Simultaneous oral administration of clarithromycin immediate-release tablets and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine concentrations. Administration of clarithromycin and zidovudine should be separated by at least two hours [see Pharmacokinetics (12.3) ].
Calcium Channel Blockers:
 
Use With Caution Verapamil: Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent verapamil [see Warnings and Precautions (5.4) ].
   
Amlodipine, Diltiazem: [see Warnings and Precautions (5.4) ]
 
Nifedipine: Nifedipine is a substrate for CYP3A. Clarithromycin and other macrolides are known to inhibit CYP3A. There is potential of CYP3A-mediated interaction between nifedipine and clarithromycin. Hypotension and peripheral edema were observed when clarithromycin was taken concomitantly with nifedipine [see Warnings and Precautions (5.4) ].
Ergot Alkaloids:
 
Contraindicated Ergotamine, Dihydroergotamine: Postmarketing reports indicate that co-administration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system [see Contraindications (4.6) ].
Gastroprokinetic Agents:
 
Contraindicated Cisapride: [see Contraindications (4.2) ]
HMG-CoA Reductase Inhibitors:
   
Contraindicated Lovastatin, Simvastatin, Atorvastatin, Pravastatin, Fluvastatin: [see Contraindications (4.5) and Warnings and Precautions (5.4) ]
   
Use With Caution
 
No Dose Adjustment
Hypoglycemic Agents:
       
Use With Caution Nateglinide, Pioglitazone, Repaglinide, Rosiglitazone: [see Warnings and Precautions (5.4) and Adverse Reactions (6.2) ]
 
Insulin: [see Warnings and Precautions (5.4) and Adverse Reactions (6.2) ]
Immunosuppressants:
 
Use With Caution Cyclosporine: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with cyclosporine.
 
Tacrolimus: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with tacrolimus.
Phosphodiesterase Inhibitors:
     
Use With Caution Sildenafil, Tadalafil, Vardenafil: Each of these phosphodiesterase inhibitors is primarily metabolized by CYP3A, and CYP3A will be inhibited by concomitant administration of clarithromycin. Co-administration of clarithromycin with sildenafil, tadalafil, or vardenafil will result in increased exposure of these phosphodiesterase inhibitors. Co-administration of these phosphodiesterase inhibitors with clarithromycin is not recommended. Increased systemic exposure of these drugs may occur with clarithromycin; reduction of dosage for phosphodiesterase inhibitors should be considered (see their respective prescribing information).
Proton Pump Inhibitors:
 
No Dose Adjustment Omeprazole: The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when co-administered with clarithromycin as a result of increased omeprazole exposures [see Pharmacokinetics (12.3) ] (see also Omeprazole under “Drugs That Affect Clarithromycin” in the table below).
Xanthine Derivatives:
 
Use With Caution Theophylline: Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serum theophylline concentrations [see Pharmacokinetics (12.3) ]. Monitoring of serum theophylline concentrations should be considered for patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range.
Triazolobenzodiazepines and Other Related Benzodiazepines:
 
Use With Caution Midazolam: When oral midazolam is co-administered with clarithromycin, dose adjustments may be necessary and possible prolongation and intensity of effect should be anticipated [see Warnings and Precautions (5.4) and Pharmacokinetics (12.3) ].
   
Triazolam, Alprazolam: Caution and appropriate dose adjustments should be considered when triazolam or alprazolam is co-administered with clarithromycin. There have been postmarketing reports of drug interactions and central nervous system (CNS) effects (e.g., somnolence and confusion) with the concomitant use of clarithromycin and triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested. In postmarketing experience, erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines.
     
No Dose Adjustment Temazepam, Nitrazepam, Lorazepam: For benzodiazepines which are not metabolized by CYP3A (e.g., temazepam, nitrazepam, lorazepam), a clinically important interaction with clarithromycin is unlikely.
Cytochrome P450 Inducers:
 
Use With Caution Rifabutin: Concomitant administration of rifabutin and clarithromycin resulted in an increase in rifabutin, and decrease in clarithromycin serum levels together with an increased risk of uveitis (see Rifabutin under “Drugs That Affect Clarithromycin” in the table below).
Other Drugs Metabolized by CYP3A:
             
Use With Caution There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with alfentanil, methylprednisolone, cilostazol, bromocriptine, vinblastine, phenobarbital, and St. John’s Wort.
Other Drugs Metabolized by CYP450 Isoforms Other than CYP3A:
     
Use With Caution There have been postmarketing reports of interactions of clarithromycin with drugs not thought to be metabolized by CYP3A, including hexobarbital, phenytoin, and valproate.
Drugs that Affect Clarithromycin
Drug(s) that Affect
the Pharmacokinetics
of Clarithromycin
Recommendation Comments
Antifungals:
 
Use With Caution Itraconazole: Itraconazole may increase the plasma concentrations of clarithromycin. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions (see also Itraconazole under “Drugs That Are Affected By Clarithromycin” in the table above).
Antivirals:
 
Use With Caution Atazanavir: When clarithromycin is co-administered with atazanavir, the dose of clarithromycin should be decreased by 50% [see Clinical Pharmacology (12.3) ]. Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with atazanavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium complex. Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.
   
Ritonavir: Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with ritonavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium [see Pharmacokinetics (12.3) ]. Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.
 
Saquinavir: When saquinavir is co-administered with ritonavir, consideration should be given to the potential effects of ritonavir on clarithromycin (refer to ritonavir above) [see Pharmacokinetics (12.3) ].
 
Etravirine: Clarithromycin exposure was decreased by etravirine; however, concentrations of the active metabolite, 14-OH-clarithromycin, were increased. Because 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered; therefore alternatives to clarithromycin should be considered for the treatment of MAC.
   
No Dose Adjustment
Proton Pump Inhibitors:
 
Use With Caution Omeprazole: Clarithromycin concentrations in the gastric tissue and mucus were also increased by concomitant administration of omeprazole [see Pharmacokinetics (12.3) ].
Miscellaneous Cytochrome P450 Inducers:
         
Use With Caution Inducers of CYP3A enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine will increase the metabolism of clarithromycin, thus decreasing plasma concentrations of clarithromycin, while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. Alternative antibacterial treatment should be considered when treating patients receiving inducers of CYP3A. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with rifabutin (see Rifabutin under “Drugs That Are Affected By Clarithromycin” in the table above).


Table name:
AED Co-administered
AED Concentration
Topiramate Concentration
Phenytoin
NCor25%increasea
48%decrease
Carbamazepine(CBZ)
NC
40%decrease
CBZepoxideb
NC 
            NE
Valproic acid
11%decrease
14%decrease
Phenobarbital
NC
            NE
Primidone
NC
           NE
Lamotrigine
NCatTPM dosesupto400  mg/day 
         13%decrease


Table name:
Table 4. Mean (95% C.I.) maximal change in baseline in systolic blood pressure (mmHg) following vardenafil 10 and 20 mg in healthy volunteers on daily alpha-blocker therapy
Dosing of Vardenafil and Alpha-Blocker Separated by 6 Hours Simultaneous dosing of Vardenafil and Alpha-Blocker
Alpha-Blocker Vardenafil
10 mg
Placebo-Subtracted
Vardenafil
20 mg
Placebo-Subtracted
Vardenafil
10 mg
Placebo-Subtracted
Vardenafil
20 mg
Placebo-Subtracted
Terazosin
10 mg daily
Standing SBP -7 (-10, -3) -11 (-14, -7) -23 (-31, 16) Due to the sample size, confidence intervals may not be an accurate measure for these data. These values represent the range for the difference. -14 (-33, 11)
Supine SBP -5 (-8, -2) -7 (-11, -4) -7 (-25, 19) -7 (-31, 22)
Tamsulosin
0.4 mg daily
Standing SBP -4 (-8, -1) -8 (-11, -4) -8 (-14, -2) -8 (-14, -1)
Supine SBP -4 (-8, 0) -7 (-11, -3) -5 (-9, -2) -3 (-7, 0)


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion–the reduction is not sustained; therefore, hypothyroidism does not occur
  Dopamine / Dopamine Agonists
Glucocorticoids
Octreotide
  Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
  Aminoglutethimide
Amiodarone
Iodide(including iodine-containing
  Radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
  Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients.  The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
  Amiodarone
Iodide(including iodine-containing   
  Radiographic contrast agents)
  Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma).  Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
  Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
  Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism.  Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents.  Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport  - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
  Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
  Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
  Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
  Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4, and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result  in hypothyroidism
  Carbamazepine
Hydantoins
Phenobarbital
Rifampin
  Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5’-deiodinase activity
  Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
  Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4  levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
  Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
  Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
  Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors
  (SSRIs; e.g., Sertraline)
  Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of  tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
  Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
  Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
  Cardiac Glycosides   Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
  Cytokines
- Interferon-α
- Interleukin-2
  Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
  Growth Hormones
- Somatrem
- Somatropin
  Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
  Ketamine   Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
  Methylxanthine Bronchodilators
- (e.g., Theophylline)
  Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
  Radiographic Agents   Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
  Sympathomimetics   Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
  Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
  These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
* For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Interacting Agents
Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol
Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone
Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine
Do not exceed 20 mg simvastatin daily
Lomitapide
For patients with HoFH, do not exceed 20 mg simvastatin daily*
Grapefruit juice
Avoid grapefruit juice


Table name: Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, coadministration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.During concomitant use of meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Table 3 Clinically Significant Drug Interactions with Meloxicam
Drugs that Interfere with Hemostasis
Clinical Impact:
Intervention: Monitor patients with concomitant use of meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].
Intervention: Concomitant use of meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. Meloxicam is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, or Beta-Blockers
Clinical Impact:
Intervention:
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam.
Intervention: During concomitant use of meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [see Clinical Pharmacology (12.3)].
Intervention: During concomitant use of meloxicam and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of meloxicam and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of meloxicam and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of meloxicam and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention: The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended.


Table name:
Calcium Channel Blockers Antifungals Antibiotics Glucocorticoids Other Drugs
diltiazem nicardipine verapamil fluconazole itraconazole ketoconazole voriconazole azithromycin clarithromycin erythromycin quinupristin/ dalfopristin methylprednisolone allopurinol amiodarone bromocriptine colchicine danazol imatinib metoclopramide nefazodone oral contraceptives


Table name:
 Table 4 Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions:
See Clinical Pharmacology (12.3) , Table 5 for Magnitude of Interaction.
Drug Name Effect on concentration of Nevirapine or Concomitant drug Clinical Comment
Atazanavir/Ritonavir ↓ Atazanavir ↑ Nevirapine Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure.
Clarithromycin ↓ Clarithromycin ↑ 14-OH clarithromycin Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium- intracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.
Efavirenz ↓ Efavirenz There has been no determination of appropriate doses for the safe and effective use of this combination [see Warnings and Precautions (5.4) ].
Ethinyl estradiol and Norethindrone ↓ Ethinyl estradiol ↓ Norethindrone Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended
Fluconazole ↑Nevirapine Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine- associated adverse events.
Fosamprenavir ↓Amprenavir ↑Nevirapine Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.
Fosamprenavir/Ritonavir ↓Amprenavir ↑Nevirapine No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily.
Indinavir ↓ Indinavir Appropriate doses for this combination are not established, but an increase in the dosage of indinavir may be required.
Ketoconazole ↓ Ketoconazole Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.
Lopinavir/Ritonavir ↓Lopinavir A dose increase of lopinavir/ritonavir tablets to 500/125 mg twice-daily is recommended when used in combination with nevirapine. A dose increase of lopinavir/ritonavir oral solution to 533/133 mg twice daily with food is recommended in combination with nevirapine. In children 6 months to 12 years of age receiving lopinavir/ritonavir solution, consideration should be given to increasing the dose of lopinavir/ritonavir to 13/3.25 mg/kg for those 7 to <15 kg; 11/2.75 mg/kg for those 15 to 45 kg; up to a maximum dose of 533/133 mg twice daily. Refer to the lopinavir/ritonavir package insert for complete pediatric dosing instructions when lopinavir/ritonavir tablets are used in combination with nevirapine.
Methadone ↓ Methadone Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone- maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Nelfinavir ↓Nelfinavir M8   Metabolite ↓Nelfinavir Cmin The appropriate dose for nelfinavir in combination with nevirapine, with respect to safety and efficacy, has not been established.
Rifabutin ↑Rifabutin Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.
Rifampin ↓ Nevirapine Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Saquinavir/Ritonavir The interaction between Nevirapine
and saquinavir/ritonavir has not been evaluated
The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
Potential Drug Interactions
Drug Class Examples of Drugs
Antiarrhythmics Amiodarone, disopyramide, lidocaine Plasma concentrations may be decreased.
Anticonvulsants Carbamazepine, clonazepam, ethosuximide Plasma concentrations may be decreased.
Antifungals Itraconazole Plasma concentrations of some azole antifungals may be decreased. Nevirapine and itraconazole should not be administered concomitantly due to a potential decrease in itraconazole plasma concentrations.
Calcium channel blockers Diltiazem, nifedipine, verapamil Plasma concentrations may be decreased.
Cancer chemotherapy Cyclophosphamide Plasma concentrations may be decreased.
Ergot alkaloids Ergotamine Plasma concentrations may be decreased.
Immunosuppressants Cyclosporin, tacrolimus, sirolimus Plasma concentrations may be decreased.
Motility agents Cisapride Plasma concentrations may be decreased.
Opiate agonists Fentanyl Plasma concentrations may be decreased.
Antithrombotics Warfarin Plasma concentrations may be increased. Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.


Table name:
Table 3 Clinically Significant Drug Interactions with Meloxicam
Drugs  that  Interfere  with  Hemostasis
Clinical  Impact :
Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.
Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention :
Monitor patients with concomitant use of meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical  Impact :
Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].
Intervention :
Concomitant use of meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. Meloxicam is not a substitute for low dose aspirin for cardiovascular protection.
ACE  Inhibitors Angiotensin  Receptor  Blockers or  Beta - Blockers
Clinical  Impact :
NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).
In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention :
During concomitant use of meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical  Impact :
Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam.
Intervention :
During concomitant use of meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Lithium
Clinical  Impact :
NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [see Clinical Pharmacology (12.3)].
Intervention :
During concomitant use of meloxicam and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical  Impact :
Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention :
During concomitant use of meloxicam and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical  Impact :
Concomitant use of meloxicam and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention :
During concomitant use of meloxicam and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs  and  Salicylates
Clinical  Impact :
Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention :
The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical  Impact :
Concomitant use of meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention :
During concomitant use of meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.

Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. 

In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended.


Table name:
NA = Not available/reported
Digoxin concentrations increased greater than 50%
   Digoxin Serum   
Concentration Increase
   Digoxin AUC Increase Recommendations
Amiodarone 70% NA Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring.
Captopril 58% 39%
Clarithromycin NA 70%
Dronedarone NA 150%
Gentamicin 129-212% NA
Erythromycin 100% NA
Itraconazole 80% NA
Lapatinib NA 180%
Nitrendipine 57% 15%
Propafenone NA 60-270%
Quinidine 100% NA
Ranolazine 50% NA
Ritonavir NA 86%
Telaprevir 50% 85%
Tetracycline 100% NA
Verapamil 50-75% NA
Digoxin concentrations increased less than 50%
Atorvastatin 22% 15% Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring.
Carvedilol 16% 14%
Conivaptan 33% 43%
Diltiazem 20% NA
Indomethacin 40% NA
Nefazodone 27% 15%
Nifedipine 45% NA
Propantheline 24% 24%
Quinine NA 33%
Rabeprazole 29% 19%
Saquinavir 27% 49%
Spironolactone      25% NA
Telmisartan 20-49% NA
Ticagrelor 31% 28%
Tolvaptan 30% 20%
Trimethoprim 22-28% NA
Digoxin concentrations increased, but magnitude is unclear
Alprazolam, azithromycin, cyclosporine, diclofenac, diphenoxylate, epoprostenol, esomeprazole, ibuprofen, ketoconazole, lansoprazole, metformin, omeprazole Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin concentrations decreased
Acarbose, activated charcoal, albuterol, antacids, certain cancer chemotherapy or radiation therapy, cholestyramine, colestipol, extenatide, kaolin-pectin, meals high in bran, metoclopramide, miglitol, neomycin, penicillamine, phenytoin, rifampin, St. John’s Wort, sucralfate and sulfasalazine Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20-40% as necessary.


Table name:
Concomitant Drug Name or Drug Class Clinical Rationale Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) The concomitant use of aripiprazole with strong CYP3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)]. With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin) The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)]. With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Antihypertensive Drugs Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.8)].
Benzodiazepines(e.g., lorazepam) The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.8)]. Monitor sedation and blood pressure. Adjust dose accordingly.


Table name:
Table 3 Clinically Significant Drug Interactions with Meloxicam
Drugs  that  Interfere  with  Hemostasis
Clinical  Impact :
Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.
Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. 
Intervention
Monitor patients with concomitant use of meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see  Warnings  and  Precautions  ( 5 . 11)]. 
Aspirin 
Clinical  Impact
Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see  Warnings  and  Precautions  ( 5 . 2)]. 
Intervention
Concomitant use of meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see  Warnings  and  Precautions  ( 5 . 11)]. 

Meloxicam is not a substitute for low dose aspirin for cardiovascular protection. 
ACE  Inhibitors Angiotensin  Receptor  Blockers or  Beta - Blockers 
Clinical  Impact

NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). 
In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. 
Intervention

During concomitant use of meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. 
During concomitant use of meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see  Warnings  and  Precautions  ( 5 . 6)]. 
When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. 
Diuretics 

Clinical  Impact

Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. 
Intervention

During concomitant use of meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see  Warnings  and  Precautions  ( 5 . 6)]. 
Lithium 
Clinical  Impact

NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [see  Clinical  Pharmacology  ( 12 . 3)]. 
Intervention

During concomitant use of meloxicam and lithium, monitor patients for signs of lithium toxicity. 
Methotrexate 
Clinical  Impact

Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention

During concomitant use of meloxicam and methotrexate, monitor patients for methotrexate toxicity. 
Cyclosporine 

Clinical  Impact

Concomitant use of meloxicam and cyclosporine may increase cyclosporine’s nephrotoxicity. 
Intervention

During concomitant use of meloxicam and cyclosporine, monitor patients for signs of worsening renal function. 
NSAIDs  and  Salicylates 

Clinical  Impact

Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see  Warnings  and  Precautions  ( 5 . 2)]. 
Intervention

The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended. 
Pemetrexed 

Clinical  Impact

Concomitant use of meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). 
Intervention

During concomitant use of meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended. 


Table name:
Alcohol
Clinical Impact: The concomitant use of alcohol with Oxymorphone Hydrochloride Tablets can result in an increase of oxymorphone plasma levels and potentially fatal overdose of oxymorphone.
Intervention: Instruct patients not to consume alcoholic beverages or use prescription or non- prescription products containing alcohol while on Oxymorphone Hydrochloride Tablets therapy [see Clinical Pharmacology 12.3) ].
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines and other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [Warnings and Precautions (5.4)].
Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Oxymorphone Hydrochloride Tablets if serotonin syndrome is suspected.
Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)]. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
Intervention: The use of Oxymorphone Hydrochloride Tablets is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples: phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact: May reduce the analgesic effect of Oxymorphone Hydrochloride Tablets and/or precipitate withdrawal symptoms.
Intervention: Avoid concomitant use.
Examples: butorphanol, nalbuphine, pentazocine, buprenorphine,
Muscle Relaxants
Clinical Impact: Oxymorphone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Oxymorphone Hydrochloride Tablets and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when Oxymorphone Hydrochloride Tablets are used concomitantly with anticholinergic drugs.
Anticholinergic Drugs
Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when Oxymorphone Hydrochloride Tablets are used concomitantly with anticholinergic drugs.
Cimetidine
Clinical Impact: Cimetidine can potentiate opioid-induced respiratory depression.
Intervention: Monitor patients for respiratory depression when Oxymorphone Hydrochloride Tablets and cimetidine are used concurrently.
Anticholinergic Drugs
Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when Oxymorphone Hydrochloride Tablets are used concomitantly with anticholinergic drugs.


Table name:
*Not administered but an active metabolite of carbamazepine.
 **No significant effect.
Table 2 Steady-State Plasma Concentrations of Felbamate When Coadministered With Other AEDs 
 AED Coadministered  AED Concentration  Felbamate Concentration
 Phenytoin  ↑  ↓
 Valproate  ↑  ↔**
 Carbamazepine (CBZ)
     *CBZ epoxide
 ↓
 ↓
      Phenobarbital  ↑  ↓


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7.1, 7.2, 7.3, 7.4)
Interacting Agents Prescribing Recommendations
   Itraconazole, ketoconazole, erythromycin, clarithromycin, 
   telithromycin, HIV protease inhibitors, nefazodone
   Avoid simvastatin
   Gemfibrozil, cyclosporine, danazol
   Do not exceed 10 mg simvastatin daily
   Amiodarone, verapamil
   Do not exceed 20 mg simvastatin daily
   Diltiazem    Do not exceed 40 mg simvastatin daily
   Grapefruit juice
   Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Figure 2: Effect of venlafaxine on the pharmacokinetics interacting drugs and their active metabolites.


Table name:
Table 6: Effects of Other Drugs/Substances on ASTAGRAF XLa
a   ASTAGRAF XL dosage adjustment recommendation based on observed effect of coadministered drug on tacrolimus exposures [see Clinical Pharmacology (12.3)], literature reports of altered tacrolimus exposures, or the other drug’s known CYP3A inhibitor/inducer status
b   High dose or double strength grapefruit juice is a strong CYP3A inhibitor; low dose or single strength grapefruit juice is a moderate CYP3A inhibitor
c   Strong CYP3A inhibitor/inducer, based on reported effect on exposures to tacrolimus along with supporting in vitro CYP3A inhibitor/inducer data, or based on drug-drug interaction studies with midazolam (sensitive CYP3A probe substrate)
Drug/Substance Class or Name Drug Interaction Effect Recommendations
Grapefruit or grapefruit juiceb May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see Warnings and Precautions (5.7, 5.10, 5.11)] Avoid grapefruit or grapefruit juice
Alcohol May increase the rate of tacrolimus release and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation ) [see Warnings and Precautions (5.7, 5.10, 5.11)] Avoid alcoholic beverages
Strong CYP3A Inducersc:     Antimycobacterials (e.g., rifampin, rifabutin), anticonvulsants (e.g., phenytoin, carbamazepine and phenobarbital), St John’s Wort May decrease tacrolimus whole blood trough concentrations and increase the risk of rejection [see Warnings and Precautions (5.10)] Increase ASTAGRAF XL dose and monitor tacrolimus whole blood trough concentrations [see Dosage and Administration (2.3, 2.4) and Clinical Pharmacology (12.3)]
Strong CYP3A Inhibitorsc:     Protease inhibitors (e.g, nelfinavir, telaprevir, boceprevir, ritonavir), azole antifungals (e.g., voriconazole, posaconazole, itraconazole, ketoconazole), antibiotics (e.g., clarithromycin, troleandomycin, chloramphenicol), nefazodone, schisandra sphenanthera extracts May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see Warnings and Precautions (5.7, 5.10, 5.11)] Reduce ASTAGRAF XL dose (for voriconazole and posaconazole, give one-third of the original dose) and adjust dose based on tacrolimus whole blood trough concentrations [see Dosage and Administration (2.3, 2.4) and Clinical Pharmacology (12.3)]
Mild or Moderate CYP3A Inhibitors:     Clotrimazole, antibiotics (e.g., erythromycin, fluconazole), calcium channel blockers (e.g., verapamil, diltiazem, nifedipine, nicardipine), amiodarone, danazol, ethinyl estradiol, cimetidine, lansoprazole and omeprazole May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see Warnings and Precautions (5.7, 5.10, 5.11)] Monitor tacrolimus whole blood trough concentrations and reduce ASTAGRAF XL dose if needed [see Dosage and Administration (2.3, 2.4) and Clinical Pharmacology (12.3)]
Other drugs, such as:     Magnesium and aluminum hydroxide antacids

    Metoclopramide
May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see Warnings and Precautions (5.7, 5.10, 5.11)] Monitor tacrolimus whole blood trough concentrations and reduce ASTAGRAF XL dose if needed [see Dosage and Administration (2.3, 2.4) and Clinical Pharmacology (12.3)]
Mild or Moderate CYP3A Inducers     Methylprednisolone, prednisone May decrease tacrolimus concentrations Monitor tacrolimus whole blood trough concentrations and adjust ASTAGRAF XL dose if needed [see Dosage and Administration (2.3, 2.4)]


Table name:
Concomitant Drug Name Effect of Concomitant Drug on Carbamazepine Clinical Recommendation
Aprepitant, cimetidine, ciprofloxacin, danazol, diltiazem, delavirdine, macrolides, erythromycin, troleandomycin, clarithromycin, fluoxetine, fluvoxamine, trazodone, olanzapine, loratadine, terfenadine, omeprazole, oxybutynin, dantrolene, isoniazid, niacinamide, nicotinamide, ibuprofen, propoxyphene, azoles (e.g., ketaconazole, itraconazole, fluconazole, voriconazole), acetazolamide, verapamil, ticlopidine, grapefruit juice, protease inhibitors Increase in carbamazepine level (by CYP3A4 inhibition) Closely monitor carbamazepine levels; dosage adjustment may be required
Cisplatin, doxorubicin HCl, felbamate, fosphenytoin, rifampin, phenobarbital, phenytoin, primidone, methsuximide, theophylline, aminophylline Decrease in carbamazepine level (by CYP3A4 induction)
Loxapine, quetiapine and valproic acid Decrease in carbamazepine level and increase in metabolite (carbamazepine-10,11-epoxide) levels (both by inhibition of human microsomal epoxide hydrolase) Closely monitor carbamazepine levels; dosage adjustment may be required


Table name:
Table 2: Clinically Relevant Interactions Affecting Drugs Co-Administered with Rabeprazole Sodium Delayed-Release Tablets
Antiretrovirals 
Clinical Impact: 

The effect of PPI on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. 

•  Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir, and nelfinavir) when used concomitantly with rabeprazole may reduce antiviral effect and promote the
 development of drug resistance. 

•  Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with rabeprazole may increase toxicity.

•  There are other antiretroviral drugs which do not result in clinically relevant interactions with rabeprazole. 
Rilpivirine-containing products: Concomitant use with rabeprazole sodium delayed-release tablets are contraindicated [see CONTRAINDICATIONS (4)]. See prescribing information.
Atazanavir: See prescribing information for atazanavir for dosing information. 
Intervention: 
Nelfinavir: Avoid concomitant use with rabeprazole sodium delayed-release tablets. See prescribing information for nelfinavir. 
Saquinavir: See the prescribing information for saquinavir and monitor for potential saquinavir toxicities. 
Other antiretrovirals: See prescribing information. 
Warfarin 
Clinical Impact: 

Increased INR and prothrombin time in patients receiving PPIs, including rabeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal  bleeding and even death [see WARNINGS AND PRECAUTIONS (5.2)].
Intervention: 
Monitor INR and prothrombin time. Dose adjustment of warfarin may be needed to maintain target INR range. See prescribing information for warfarin. 
Methotrexate 
Clinical Impact: 

Concomitant use of rabeprazole with methotrexate (primarily at high dose) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate,  possibly leading to methotrexate toxicities. No formal drug interaction studies of methotrexate with PPIs have been conducted [see WARNINGS AND PRECAUTIONS (5.9)].
Intervention: 

A temporary withdrawal of rabeprazole sodium delayed-release tablets may be considered in some patients receiving high dose methotrexate administration. 
Digoxin 
Clinical Impact: 
Potential for increased exposure of digoxin [see CLINICAL PHARMACOLOGY (12.3)].
Intervention: 
Monitor digoxin concentrations. Dose adjustment of digoxin may be needed to maintain therapeutic drug concentrations. See prescribing information for digoxin. 
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole, itraconazole) 
Clinical Impact: 
Rabeprazole can reduce the absorption of drugs due to its effect on reducing intragastric acidity. 
Intervention: 
Mycophenolate mofetil (MMF): Co-administration of PPIs in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, 
mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in 
transplant patients receiving PPIs and MMF. Use rabeprazole sodium delayed-release tablets with caution in transplant patients receiving MMF. 

See the prescribing information for other drugs dependent on gastric pH for absorption. 
Combination Therapy with Clarithromycin and Amoxicillin 
Clinical Impact: 
Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated.

Amoxicillin also has drug interactions. 
Intervention: 
See CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS in prescribing information for clarithromycin. See DRUG INTERACTIONS in prescribing information for amoxicillin.


Table name:
Table 6: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies [see Clinical Pharmacology (12.3) (Tables 12 and 13) for magnitude of interaction]
Concomitant Drug Class:
Drug Name
Effect on
Concentration
Clinical Comment
HIV Antiviral Agents: Reverse Transcriptase Inhibitors
Delavirdine ↑ nelfinavir (Cmin)
↓ delavirdine
Concentrations of nelfinavir were increased while concentrations of delavirdine were decreased when the two agents were coadministered. Appropriate doses of the combination, with respect to safety and efficacy, have not been established.
Nevirapine ↓ nelfinavir (Cmin) Concentrations of nelfinavir were decreased when coadministered with nevirapine. An appropriate dose of nelfinavir with respect to safety and efficacy has not been established.
Didanosine ↔ nelfinavir There was no change in nelfinavir concentration when coadministered with didanosine. However, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after VIRACEPT (given with food).
HIV Antiviral Agents: Protease Inhibitors
Indinavir ↑ nelfinavir
↑ indinavir
Concentrations of both indinavir and nelfinavir were increased when the two agents were coadministered. Appropriate doses for these combinations, with respect to safety and efficacy, have not been established.
Ritonavir ↑ nelfinavir
↔ ritonavir
Concentrations of nelfinavir were increased when coadministered with ritonavir. An appropriate dose of nelfinavir for this combination, with respect to safety and efficacy, has not been established.
Saquinavir ↑ nelfinavir
↑ saquinavir
Concentrations of both saquinavir and nelfinavir were increased when the two agents were coadministered. Appropriate doses for these combinations, with respect to safety and efficacy, have not been established.
ANTICOAGULANT
Warfarin Warfarin Coadministration of warfarin and VIRACEPT may affect concentrations of warfarin. It is recommended that the INR (international normalized ratio) be monitored carefully during treatment with VIRACEPT, especially when commencing therapy.
ANTICONVULSANTS
Carbamazepine Phenobarbital
Phenytoin

↓ nelfinavir

↓ phenytoin
Concentrations of nelfinavir may be decreased. VIRACEPT may not be effective due to decreased nelfinavir plasma concentrations in patients taking these agents concomitantly.
Phenytoin plasma/serum concentrations should be monitored; phenytoin dose may require adjustment to compensate for altered phenytoin concentration.
ANTIDEPRESSANT
Trazodone ↑ trazodone Concomitant use of trazodone and VIRACEPT may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as VIRACEPT, the combination should be used with caution and a lower dose of trazodone should be considered.
ANTIGOUT
Colchicine ↑ colchicines Patients with renal or hepatic impairment should not be given colchicine with VIRACEPT due to the risk of colchicine toxicity.

Treatment of gout flares –
co- administration of colchicine in patients on VIRACEPT:

0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days.

Prophylaxis of gout-flares –
coadministration of colchicine in patients on VIRACEPT:


If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.
If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.

Treatment of familial Mediterranean fever (FMF)– coadministration of colchicine in patients on VIRACEPT:

Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
ANTIMYCOBACTERIAL
Rifabutin ↑ rifabutin
↓ nelfinavir
  (750 mg TID)
↔ nelfinavir
  (1250 mg BID)
It is recommended that the dose of rifabutin be reduced to one-half the usual dose when administered with VIRACEPT; 1250 mg BID is the preferred dose of VIRACEPT when coadministered with rifabutin.
ENDOTHELIN RECEPTOR ANTAGONIST
Bosentan ↑ bosentan Concentrations of bosentan may be increased when coadministered with VIRACEPT. Coadministration of bosentan in patients on VIRACEPT or coadministration of VIRACEPT in patients on bosentan:
Start at or adjust bosentan to 62.5 mg once daily or every other day based upon individual tolerability.
HMG-CoA REDUCTASE INHIBITORS
Atorvastatin
Rosuvastatin
↑ atorvastatin
↑ rosuvastatin
Titrate atorvastatin dose carefully and use the lowest necessary dose; do not exceed atorvastatin 40 mg/day.
IMMUNOSUPPRESSANTS
Cyclosporine
Tacrolimus
Sirolimus
↑ immuno-suppressants
↑ nelfinavir
Concentrations of these immunosuppressants and nelfinavir may be increased by coadministration of these agents with nelfinavir.
INHALED BETA AGONIST
Salmeterol ↑ salmeterol Concurrent administration of salmeterol with VIRACEPT is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
INHALED/NASAL STEROID
Fluticasone ↑ fluticasone Concomitant use of fluticasone propionate and VIRACEPT may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use.
MACROLIDE ANTIBIOTIC
Azithromycin ↑ azithromycin Dose adjustment of azithromycin is not recommended, but close monitoring for known side effects such as liver enzyme abnormalities and hearing impairment is warranted.
NARCOTIC ANALGESIC
Methadone ↓ methadone Concentrations of methadone were decreased when coadministered with VIRACEPT. Dosage of methadone may need to be increased when coadministered with VIRACEPT.
HORMONAL CONTRACEPTIVES
Ethinyl estradiol
Norethindrone
↓ ethinyl estradiol
↓ norethindrone
Concentrations of ethinyl estradiol and norethindrone were decreased when coadministered with VIRACEPT. Alternative or additional contraceptive measures should be used when oral contraceptives containing ethinyl estradiol or norethindrone and VIRACEPT are coadministered.
PDE5 INHIBITORS
Sildenafil
Vardenafil
Tadalafil
↑ PDE5 Inhibitors Concomitant use of PDE5 inhibitors and VIRACEPT should be undertaken with caution.

May result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism.

Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH):

• Use of sildenafil (REVATIO) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) [see Contraindications (4)].

• The following dose adjustments are recommended for use of tadalafil (ADCIRCA™) with VIRACEPT:

Coadministration of ADCIRCA in patients on VIRACEPT or coadministration of VIRACEPT in patients on ADCIRCA:

Start at or adjust ADCIRCA to 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Use of PDE5 inhibitors for erectile dysfunction:

Sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg in 24 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours, is recommended. Use with increased monitoring for adverse events.
PROTON PUMP INHIBITORS
Omeprazole ↓ nelfinavir Omeprazole decreases the plasma concentrations of nelfinavir. Concomitant use of proton pump inhibitors and VIRACEPT may lead to a loss of virologic response and development of resistance.
ANTIPSYCHOTICS
Quetiapine ↑ quetiapine Initiation of VIRACEPT in patients taking quetiapine:
Consider alternative antiretroviral therapy to avoid increases in quetiapine drug exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring.
Initiation of quetiapine in patients taking VIRACEPT:
Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.


Table name:
Table 14: Clinically Important Drug Interactions: Effect of other Drugs on Guanfacine Extended-Release Tablets
Concomitant Drug Name or Drug Class Clinical Rationale and Magnitude of Drug Interaction Clinical Recommendation
Strong and moderate CYP3A4 inhibitors, e.g., ketoconazole, fluconazole Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected resulting in an increase in exposure Consider dose reduction [see Dosage and administration (2.7) ]
Strong and moderate CYP3A4 inducers, e.g., rifampin, efavirenz Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected resulting in a 60% decrease in exposure Consider dose increase[see Dosage and administration (2.7) ]


Table name:
Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s) Recommendation Comments
Tizanidine Contraindicated Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)].
Theophylline Avoid Use (Plasma Exposure Likely to be Increased and Prolonged) Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions (5.6).]
Drugs Known to Prolong QT Interval Avoid Use Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.10) and Use in Specific Populations (8.5)].
Oral antidiabetic drugs Use with caution Glucose-lowering effect potentiated Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported . Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs. [see Adverse Reactions (6.1).]
Phenytoin Use with caution Altered serum levels of phenytoin (increased and decreased) To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after coadministration of ciprofloxacin with phenytoin.
Cyclosporine Use with caution (transient elevations in serum creatinine) Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs Use with caution (Increase in anticoagulant effect) The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole Use with caution Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after coadministration with ciprofloxacin [see Warnings and Precautions (5.15)].
Clozapine Use with caution Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs Use with caution Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil Use with caution 2-fold increase in exposure Monitor for sildenafil toxicity (see Pharmacokinetics -(12.3)-] .
Duloxetine Avoid Use 5-fold increase in duloxetine exposure If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx ® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products) Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2)]. Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels) Potentiation of ciprofloxacin toxicity may occur.


Table name:
Table 2: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 5 mg in BPH patients on stable alpha-blocker therapy (Study 1)
Alpha-Blocker Simultaneous dosing of Vardenafil 5 mg
and Alpha-Blocker,
Placebo-Subtracted
Dosing of Vardenafil 5 mg
and Alpha-Blocker
Separated by 6 Hours,
Placebo-Subtracted
Terazosin
5 or 10 mg daily
Standing SBP -3 (-6.7, 0.1) -4 (-7.4, -0.5)
Supine SBP -4 (-6.7, -0.5) -4 (-7.1, -0.7)
Tamsulosin
0.4 mg daily
Standing SBP
Supine SBP
-6 (-9.9, -2.1)
-4 (-7.0, -0.8)
-4 (-8.3, -0.5)
-5 (-7.9, -1.7)


Table name:
Table 7 Summary of AED Interactions with Oxcarbazepine
AED Coadministered
Dose of AED (mg/day)
Oxcarbazepine Dose (mg/day)
Influence of Oxcarbazepine on AED Concentration  (Mean Change, 90% Confidence Interval)
Influence of AED on MHD Concentration  (Mean Change, 90% Confidence Interval)
Carbamazepine
400 to 2,000
900
nc¹nc denotes a mean change of less than 10%
40% decrease [CI: 17% decrease,  57% decrease]
Phenobarbital
100 to 150
600 to 1,800
14% increase [CI: 2% increase, 24% increase]
25% decrease [CI: 12% decrease,  51% decrease]
Phenytoin
250 to 500
600 to 1,800 >1,200 to 2,400
nc ²Pediatrics
up to 40% increase³Mean increase in adults at high oxcarbazepine doses[CI: 12% increase, 60% increase]
30% decrease [CI: 3% decrease,  48% decrease]
Valproic acid
400 to 2,800
600 to 1,800
nc
18% decrease [CI: 13% decrease,  40% decrease]
Lamotrigine
200
1200
nc
nc


Table name:
Antiretrovirals 
Clinical Impact: The effect of PPI on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir, and nelfinavir) when used concomitantly with rabeprazole may reduce antiviral effect and promote the development of drug resistance. Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with rabeprazole may increase toxicity. There are other antiretroviral drugs which do not result in clinically relevant interactions with rabeprazole.  
Intervention: Rilpivirine-containing products: Concomitant use with Rabeprazole Sodium Delayed-Release Tablets is contraindicated [see Contraindications (4)]. See prescribing information. Atazanavir: See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with Rabeprazole Sodium Delayed-Release Tablets. See prescribing information for nelfinavir. Saquinavir: See the prescribing information for saquinavir and monitor for potential saquinavir toxicities. Other antiretrovirals: See prescribing information.
 Warfarin
Clinical Impact: Increased INR and prothrombin time in patients receiving PPIs, including rabeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death [see Warnings and Precautions (5.2)].
Intervention: Monitor INR and prothrombin time. Dose adjustment of warfarin may be needed to maintain target INR range. See prescribing information for warfarin.
Methotrexate
Clinical Impact: Concomitant use of rabeprazole with methotrexate (primarily at high dose) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of methotrexate with PPIs have been conducted [see Warnings and Precautions (5.9)].
Intervention: A temporary withdrawal of Rabeprazole Sodium Delayed-Release Tablets may be considered in some patients receiving high dose methotrexate administration.
Digoxin
Clinical Impact: Potential for increased exposure of digoxin [see Clinical Pharmacology (12.3)].
Intervention: Monitor digoxin concentrations. Dose adjustment of digoxin may be needed to maintain therapeutic drug concentrations. See prescribing information for digoxin.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole, itraconazole)
Clinical Impact: Rabeprazole can reduce the absorption of drugs due to its effect on reducing intragastric acidity.
Intervention: Mycophenolate mofetil (MMF): Co-administration of PPIs in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving PPIs and MMF. Use Rabeprazole Sodium Delayed-Release Tablets with caution in transplant patients receiving MMF. See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact: Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions.
Intervention: See Contraindications and Warnings and Precautions in prescribing information for clarithromycin. See Drug Interactions in prescribing information for amoxicillin.


Table name:
Interacting DrugInteracting Drug InteractionInteraction
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products ( 2.4, 7.1)
Warfarin
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( 7.2)
Antidiabetic agents
Carefully monitor blood glucose ( 5.12, 7.3)


Table name:
Interacting Agents Prescribing Recommendations
Itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Amiodarone, verapamil, diltiazem Do not exceed 10 mg simvastatin daily
Amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Grapefruit juice Avoid large quantities of grapefruit juice (> 1 quart daily)


Table name:
  Interacting Drug
  Interaction
  Multivalent cation-containing
products including antacids,
metal cations or didanosine
  Absorption of levofloxacin is decreased
when the tablet formulation is taken within
2 hours of these products. (2.4, 7.1)
  Warfarin
  Effect may be enhanced. Monitor
prothrombin time, INR, watch for bleeding
(7.2)
  Antidibetic agents
  Carefully monitor blood glucose (5.12, 7.3)


Table name:
Name of the
Concomitant Drug
Change in the Concentration of Ganciclovir or
Concomitant Drug

Clinical Comment
Zidovudine
↓ Ganciclovir
↑ Zidovudine
Zidovudine and valganciclovir tablets each have the potential to cause neutropenia and anemia
Probenicid
↑ Ganciclovir
Patients taking probenicid and valganciclovir tablets should be monitored for evidence of ganciclovir toxicity
Mycophenolate  Mofetil
(MMF)
↔  Ganciclovir (in patients with normal renal function)
↔ MMF (in patients with normal renal function)
Patients with renal impairment should be monitored carefully as levels of MMF metabolites and ganciclovir may increase
Didanosine
↓ Ganciclovir
↑ Didanosine
Patients should be closely monitored for didanosine toxicity


Table name:
Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme
Inhibitors
Inducers
CYP2C9 
amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast
aprepitant, bosentan, carbamazepine, phenobarbital, rifampin 
CYP1A2 
acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton
montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking 
CYP3A4 
alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton
armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide 


Table name:
Table 3: Summary of AED Interactions with Oxcarbazepine
AED Coadministered Dose of AED
(mg/day)
Oxcarbazepine Dose
(mg/day)
Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval) Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine 400-2000 900 ncnc denotes a mean change of less than 10% 40% decrease [CI:17% decrease, 57% decrease]
Phenobarbital 100-150 600-1800 14% increase
[CI: 2% increase, 24% increase]
25% decrease
[CI:12% decrease, 51% decrease]
Phenytoin 250-500 600-1800
>1200-2400
nc , Pediatrics
up to 40% increaseMean increase in adults at high Oxcarbazepine doses
[CI: 12% increase, 60% increase]
30% decrease
[CI: 3% decrease, 48% decrease]
Valproic acid 400-2800 600-1800 nc 18% decrease
[CI:13% decrease, 40% decrease]


Table name:
Classes of Drugs
Adrenal Cortical Steroid
Inhibitors
Antacids
Antianxiety Agents
Antiarrhythmics†
Antibiotics†
Anticonvulsants†
Antidepressants†
Antihistamines
Antineoplastics†
Antipsychotic Medications
Antithyroid Drugs†
Barbiturates
Diuretics†
Enteral Nutritional
Supplements
Fungal Medications, Systemic†
Gastric Acidity and Peptic
Ulcer Agents†
Hypnotics†
Hypolipidemics†
Bile Acid-Binding Resins†
HMG-CoA Reductase Inhibitors†
Immunosuppressives
Oral Contraceptives, Estrogen
Containing
Selective Estrogen Receptor
Modulators
Steroids, Adrenocortical†
Tuberculosis Agents†
Vitamins†


Table name:
Interacting Drug Interaction
Theophylline Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin Monitor phenytoin level (7)
Methotrexate Monitor for methotrexate toxicity (7)
Cyclosporine May increase serum creatinine. Monitor serum creatinine (7)


Table name:
AED  Co - administered
AED  Concentration
Topiramate  Concentration
Phenytoin
NCor25%increase a
48%decrease
Carbamazepine(CBZ)
NC
40%decrease
CBZepoxide b
NC 
            NE
Valproic acid
11%decrease
14%decrease
Phenobarbital
NC
            NE
Primidone
NC
           NE
Lamotrigine
NCatTPM dosesupto400  mg/day 
         13%decrease


Table name:
AED  Co - administered
AED  Concentration
Topiramate  Concentration
Phenytoin
NCor25%increase a
48%decrease
Carbamazepine(CBZ)
NC
40%decrease
CBZepoxide b
NC 
            NE
Valproic acid
11%decrease
14%decrease
Phenobarbital
NC
            NE
Primidone
NC
           NE
Lamotrigine
NCatTPM dosesupto400  mg/day 
         13%decrease


Table name:
* The interaction between immediate-release nevirapine and the drug was evaluated in a clinical study. The results of drug interaction studies with immediate-release nevirapine are expected to also apply to nevirapine extended-release.
Drug Name Effect on Concentration of Nevirapine or Concomitant Drug Clinical Comment
HIV Antiviral Agents: Protease Inhibitors (PIs)
Atazanavir/Ritonavir* ↓ Atazanavir
↑ Nevirapine
Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures.
Fosamprenavir* ↓ Amprenavir
↑ Nevirapine
Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.
Fosamprenavir/Ritonavir* ↓ Amprenavir
↑ Nevirapine
No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied.
Indinavir* ↓ Indinavir The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established.
Lopinavir/Ritonavir* ↓ Lopinavir Dosing in adult patients:A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. Dosing in pediatric patients:Please refer to the Kaletra® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.
Nelfinavir* ↓ Nelfinavir M8 Metabolite
↓ Nelfinavir Cmin
The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established.
Saquinavir/ritonavir The interaction between nevirapine and saquinavir/ritonavir has not been evaluated The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz* ↓ Efavirenz The appropriate doses of these combinations with respect to safety and efficacy have not been established.
Delavirdine
Etravirine
Rilpivirine
Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial.
Hepatitis C Antiviral Agents
Boceprevir Plasma concentrations of boceprevir may be decreased due to induction of CYP3A4/5 by nevirapine. Nevirapine and boceprevir should not be coadministered because decreases in boceprevir plasma concentrations may result in a reduction in efficacy.
Telaprevir Plasma concentrations of telaprevir may be decreased due to induction of CYP3A4 by nevirapine and plasma concentrations of nevirapine may be increased due to inhibition of CYP3A4 by telaprevir. Nevirapine and telaprevir should not be coadministered because changes in plasma concentrations of nevirapine, telaprevir, or both may result in a reduction in telaprevir efficacy or an increase in nevirapine-associated adverse events.
Other Agents
Analgesics:
Methadone*
↓ Methadone Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Antiarrhythmics:
Amiodarone, disopyramide, lidocaine
Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Antibiotics:
Clarithromycin*
↓ Clarithromycin
↑ 14-OH clarithromycin
Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.
Rifabutin* ↑ Rifabutin Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.
Rifampin* ↓ Nevirapine Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Anticonvulsants:
Carbamazepine, clonazepam, ethosuximide
Plasma concentrations of nevirapine and the anticonvulsant may be decreased. Use with caution and monitor virologic response and levels of anticonvulsants.
Antifungals:
Fluconazole*
↑ Nevirapine Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events.
Ketoconazole* ↓ Ketoconazole Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.
Itraconazole ↓ Itraconazole Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug.
Antithrombotics:
Warfarin
Plasma concentrations may be increased. Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.
Calcium channel blockers: Diltiazem, nifedipine, verapamil Plasma concentrations may be decreased. Appropriate doses for these combinations have not been established.
Cancer chemotherapy: Cyclophosphamide Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Ergot alkaloids:
Ergotamine
Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Immunosuppressants: Cyclosporine, tacrolimus, sirolimus Plasma concentrations may be decreased. Appropriate doses for these combinations have not been established.
Motility agents:
Cisapride
Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Opiate agonists:
Fentanyl
Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Oral contraceptives:
Ethinyl estradiol and Norethindrone*
↓ Ethinyl estradiol
↓ Norethindrone
Despite lower ethinyl estradiol and norethindrone exposures when coadministered with nevirapine, literature reports suggest that nevirapine has no effect on pregnancy rates among HIV-infected women on combined oral contraceptives. When coadministered with nevirapine extended-release tablets, no dose adjustment of ethinyl estradiol or norethindrone is needed when used in combination for contraception When oral contraceptives are used for hormonal regulation during nevirapine extended-release tablets therapy, the therapeutic effect of the hormonal therapy should be monitored.


Table name: Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology (12.3)]. Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see Clinical Pharmacology (12.3)]. There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole.
Table 3: Clinically Relevant Interactions Affecting Drugs Co-Administered with Omeprazole and Interaction with Diagnostics
Antiretrovirals
Clinical Impact:
The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known.
Intervention:
Rilpivirine-containing products: Concomitant use with omeprazole is contraindicated [see Contraindications (4)].
 
Atazanavir: Avoid concomitant use with omeprazole. See prescribing information for atazanavir for dosing information.
 
Nelfinavir: Avoid concomitant use with omeprazole. See prescribing information for nelfinavir.
 
Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities.
 
Other antiretrovirals: See prescribing information for specific antiretroviral drugs.
Warfarin
Clinical Impact:
Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
Intervention:
Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range.
Methotrexate
Clinical Impact:
Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions (5.11)].
Intervention:
A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate.
CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam)
Clopidogrel
Clinical Impact:
Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology (12.3)].
There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel.
Intervention:
Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy [see Warnings and Precautions (5.6)].
Citalopram
Clinical Impact:
Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology (12.3)].
Intervention:
Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.
Cilostazol
Clinical Impact:
Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology (12.3)].
Intervention:
Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.
Phenytoin
Clinical Impact:
Potential for increased exposure of phenytoin.
Intervention:
Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin.
Diazepam
Clinical Impact:
Increased exposure of diazepam [see Clinical Pharmacology (12.3)].
Intervention:
Monitor patients for increased sedation and reduce the dose of diazepam as needed.
Digoxin
Clinical Impact:
Potential for increased exposure of digoxin [see Clinical Pharmacology (12.3)].
Intervention:
Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)
Clinical Impact:
Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
Intervention:
Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF [see Clinical Pharmacology (12.3)].
 
See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact:
Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions.
Intervention:
See Contraindications, Warnings and Precautions  in prescribing information for clarithromycin.
 
See Drug Interactions in prescribing information for amoxicillin.
Tacrolimus
Clinical Impact:
Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.
Intervention:
Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact:
Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions (5.10), Clinical Pharmacology (12.2)].
Intervention:
Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
Interaction with Secretin Stimulation Test
Clinical Impact:
Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention:
Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology (12.2)].
False Positive Urine Tests for THC
Clinical Impact:
There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.
Intervention:
An alternative confirmatory method should be considered to verify positive results.
Other
Clinical Impact:
There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram).
Intervention:
Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole.


Table name:

Figure 5: Mean Standing Systolic Blood Pressure Change from Baseline


Table name:
Table II. Clinically Significant Drug Interactions With Theophylline*
Drug Type Of Interaction Effect**
*    Refer to  PRECAUTIONS , Drug Interactions for further information regarding table.
**  Average effect on steady-state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.
Adenosine Theophylline blocks adenosine receptors. Higher doses of adenosine may be required to achieve desired effect.
Alcohol A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours. 30% increase
Allopurinol Decreases theophylline clearance at allopurinol doses ≥600 mg/day. 25% increase
Aminoglutethimide Increases theophylline clearance by induction of microsomal enzyme activity. 25% decrease
Carbamazepine Similar to aminoglutethimide. 30% decrease
Cimetidine Decreases theophylline clearance by inhibiting cytochrome P450 1A2. 70% increase
Ciprofloxacin Similar to cimetidine.  40% increase
Clarithromycin Similar to erythromycin. 25% increase
Diazepam Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram Decreases theophylline clearance by inhibiting hydroxylation and demethylation. 50% increase
Enoxacin Similar to cimetidine.  300% increase
Ephedrine Synergistic CNS effects. Increased frequency of nausea, nervousness, and insomnia.
Erythromycin Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3. 35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown. 30% increase
Flurazepam Similar to diazepam. Similar to diazepam.
Fluvoxamine Similar to cimetidine. Similar to cimetidine.
Halothane Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines. Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-A Decreases theophylline clearance. 100% increase
Isoproterenol (I.V.) Increases theophylline clearance. 20% decrease
Ketamine Pharmacologic May lower theophylline seizure threshold.
Lithium Theophylline increases renal lithium clearance. Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam Similar to diazepam. Similar to diazepam.
Methotrexate (MTX) Decreases theophylline clearance. 20% increase after low dose MTX, higher dose MTX may have a greater effect.
Mexiletine Similar to disulfiram. 80% increase
Midazolam Similar to diazepam. Similar to diazepam.
Moricizine Increases theophylline clearance. 25% decrease
Pancuronium Theophylline may antagonize nondepolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition. Larger dose of pancuronium may be required to achieve neuromuscular blockade.
Pentoxifylline Decreases theophylline clearance. 30% increase
Phenobarbital (PB) Similar to aminoglutethimide. 25% decrease after two weeks of concurrent Phenobarbital.
Phenytoin Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption. Serum theophylline and phenytoin concentrations decrease about 40%.
Propafenone Decreases theophylline clearance and pharmacologic interaction. 40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Propranolol Similar to cimetidine and pharmacologic interaction. 100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Rifampin Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity. 20 - 40% decrease
Sulfinpyrazone Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline. 20% decrease
Tacrine Similar to cimetidine, also increases renal clearance of theophylline. 90% increase
Thiabendazole Decreases theophylline clearance. 190% increase
Ticlopidine Decreases theophylline clearance. 60% increase
Troleandomycin Similar to erythromycin. 33 - 100% increase depending on troleandomycin dose.
Verapamil Similar to disulfiram. 20% increase


Table name:
Table 25: Clinically Important Drug Interactions with Aripiprazole:
Concomitant Drug Name or Drug Class
Clinical Rationale
Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine)     
 
The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].
With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)        
The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see  CLINICAL PHARMACOLOGY (12.3)].
With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Antihypertensive Drugs
Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.
Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.8)].
Benzodiazepines (e.g., lorazepam)
The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.8)].
Monitor sedation and blood pressure. Adjust dose accordingly.
 


Table name:
Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug Dosing Schedule Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio Change relative to reference) Risperidone Dose Recommendation
Coadministered Drug Risperidone AUC Cmax
Enzyme (CYP2D6) Inhibitors
Fluoxetine 20 mg/day 2 or 3 mg twice daily 1.4 1.5 Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine 10 mg/day 4 mg/day 1.3 - Re-evaluate dosing. Do not exceed 8 mg/day
20 mg/day 4 mg/day 1.6 -
40 mg/day 4 mg/day 1.8 -
Enzyme (CYP3A/PgP inducers) Inducers
Carbamazepine 573 ± 168 mg/day 3 mg twice daily 0.51 0.55 Titrate dose upwards. Do not exceed twice the patient's usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine 150 mg twice daily 1 mg single dose 1.2 1.4 Dose adjustment not needed
Cimetidine 400 mg twice daily 1 mg single dose 1.1 1.3 Dose adjustment not needed
Erythromycin 500 mg four times daily 1 mg single dose 1.1 0.94 Dose adjustment not needed
Other Drugs
Amitriptyline 50 mg twice daily 3 mg twice daily 1.2 1.1 Dose adjustment not needed


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.10, 7.3)


Table name:
Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol, famotidine nizatidine
systemic and inhaled felodipine norfloxacin
amoxicillin finasteride ofloxacin
ampicillin, hydrocortisone omeprazole
with or without isoflurane prednisone, prednisolone
sulbactam isoniazid ranitidine
atenolol isradipine rifabutin
azithromycin influenza vaccine roxithromycin
caffeine, ketoconazole sorbitol
  dietary ingestion lomefloxacin (purgative doses do not
cefaclor mebendazole inhibit theophylline
co-trimoxazole medroxyprogesterone absorption)
(trimethoprim and methylprednisolone sucralfate
sulfamethoxazole) metronidazole terbutaline, systemic
diltiazem metoprolol terfenadine
dirithromycin nadolol tetracycline
enflurane nifedipine tocainide


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products ( 2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( 7.2)
Antidiabetic agents Carefully monitor blood glucose ( 5.11, 7.3)


Table name:
Interacting Agents Prescribing Recommendations 
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone Avoid simvastatin 
Gemfibrozil, cyclosporine,danazol  Do not exceed 10 mg simvastatindaily 
Amiodarone, verapamil Do not exceed 20 mg simvastatin daily 
Diltiazem Do not exceed 40 mg simvastatin daily
Grapefruit juice Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
DRUG DESCRIPTION OF INTERACTION
Corticosteroids Decreases plasma salicylate level; tapering doses of steroids may promote salicylism.
Acidifying Agents Increases plasma salicylate level.
Alkanizing Agents Decreased plasma salicylate levels.


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
 Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration  Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
 Drugs that may alter T 4 and T 3 metabolism
 Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
 Table 4 Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions:
See Clinical Pharmacology (12.3) , Table 5 for Magnitude of Interaction.
Drug Name Effect on concentration of Nevirapine or Concomitant drug Clinical Comment
Atazanavir/Ritonavir ↓ Atazanavir ↑ Nevirapine Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure.
Clarithromycin ↓ Clarithromycin ↑ 14-OH clarithromycin Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium- intracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.
Efavirenz ↓ Efavirenz There has been no determination of appropriate doses for the safe and effective use of this combination [see Warnings and Precautions (5.4) ].
Ethinyl estradiol and Norethindrone ↓ Ethinyl estradiol ↓ Norethindrone Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended
Fluconazole ↑Nevirapine Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine- associated adverse events.
Fosamprenavir ↓Amprenavir ↑Nevirapine Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.
Fosamprenavir/Ritonavir ↓Amprenavir ↑Nevirapine No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily.
Indinavir ↓ Indinavir Appropriate doses for this combination are not established, but an increase in the dosage of indinavir may be required.
Ketoconazole ↓ Ketoconazole Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.
Lopinavir/Ritonavir ↓Lopinavir A dose increase of lopinavir/ritonavir tablets to 500/125 mg twice-daily is recommended when used in combination with nevirapine. A dose increase of lopinavir/ritonavir oral solution to 533/133 mg twice daily with food is recommended in combination with nevirapine. In children 6 months to 12 years of age receiving lopinavir/ritonavir solution, consideration should be given to increasing the dose of lopinavir/ritonavir to 13/3.25 mg/kg for those 7 to <15 kg; 11/2.75 mg/kg for those 15 to 45 kg; up to a maximum dose of 533/133 mg twice daily. Refer to the lopinavir/ritonavir package insert for complete pediatric dosing instructions when lopinavir/ritonavir tablets are used in combination with nevirapine.
Methadone ↓ Methadone Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone- maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Nelfinavir ↓Nelfinavir M8   Metabolite ↓Nelfinavir Cmin The appropriate dose for nelfinavir in combination with nevirapine, with respect to safety and efficacy, has not been established.
Rifabutin ↑Rifabutin Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.
Rifampin ↓ Nevirapine Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Saquinavir/Ritonavir The interaction between Nevirapine
and saquinavir/ritonavir has not been evaluated
The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
Potential Drug Interactions
Drug Class Examples of Drugs
Antiarrhythmics Amiodarone, disopyramide, lidocaine Plasma concentrations may be decreased.
Anticonvulsants Carbamazepine, clonazepam, ethosuximide Plasma concentrations may be decreased.
Antifungals Itraconazole Plasma concentrations of some azole antifungals may be decreased. Nevirapine and itraconazole should not be administered concomitantly due to a potential decrease in itraconazole plasma concentrations.
Calcium channel blockers Diltiazem, nifedipine, verapamil Plasma concentrations may be decreased.
Cancer chemotherapy Cyclophosphamide Plasma concentrations may be decreased.
Ergot alkaloids Ergotamine Plasma concentrations may be decreased.
Immunosuppressants Cyclosporin, tacrolimus, sirolimus Plasma concentrations may be decreased.
Motility agents Cisapride Plasma concentrations may be decreased.
Opiate agonists Fentanyl Plasma concentrations may be decreased.
Antithrombotics Warfarin Plasma concentrations may be increased. Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.


Table name:
Table 1: Drugs that may have their plasma concentrations increased by itraconazole
Drug Class
Contraindicated
Not Recommended
Use with Caution
Comments
 
Under no circumstances is the drug to be coadministered with itraconazole, and up to two weeks after discontinuation of treatment with itraconazole.  
 
It is recommended that the use of the drug be avoided during and up to two weeks after discontinuation of treatment with itraconazole, unless the benefits outweigh the potentially increased risks of side effects. If coadministration cannot be avoided, clinical monitoring for signs or symptoms of increased or prolonged effects or side effects of the interacting drug is recommended, and its dosage be reduced or interrupted as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured. The label of the coadministered drug should be consulted for information on dose adjustment and adverse effects.  
Careful monitoring is recommended when the drug is coadministered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of the interacting drug, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured. The label of the coadministered drug should be consulted for information on dose adjustment and adverse effects.  
 
Alpha Blockers
 
tamsulosin
 
 
Analgesics
 
methadone
 
 
alfentanil,
buprenorphine IV and sublingual,
fentanyl,
oxycodone,
sufentanil
 
Methadone: The potential increase in plasma concentrations of methadone when coadministered with itraconazole may increase the risk of serious cardiovascular events including QTc prolongation and torsade de pointes.
Fentanyl: The potential increase in plasma concentrations of fentanyl when coadministered with itraconazole may increase the risk of potentially fatal respiratory depression.
Sufentanil: No human pharmacokinetic data of an interaction with itraconazole are available. In vitro data suggest that sufentanil is metabolized by CYP3A4 and so potentially increased sufentanil plasma concentrations would be expected when coadministered with itraconazole.
Antiarrhythmics
disopyramide,
dofetilide,
dronedarone,
quinidine
 
digoxin
Disopyramide, dofetilide, dronedarone, quinidine: The potential increase in plasma concentrations of these drugs when coadministered with itraconazole may increase the risk of serious cardiovascular events including QTc prolongation.
Antibacterials
 
telithromycin, in subjects with severe renal impairment or severe hepatic impairment
rifabutin
telithromycin
Telithromycin: The potential increase in plasma concentrations of telithromycin in subjects with severe renal impairment or severe hepatic impairment, when coadministered with itraconazole may increase the risk of serious cardiovascular events including QT prolongation and torsade de pointes.
Rifabutin: See also under ‘Drugs that may decrease itraconazole plasma concentrations’.
Anticoagulants and Antiplatelet Drugs
ticagrelor
apixaban,
rivaroxaban
coumarins,
cilostazol,
dabigatran
Ticagrelor: The potential increase in plasma concentrations of ticagrelor may increase the risk of bleeding.
Coumarins: Itraconazole may enhance the anticoagulant effect of coumarin-like drugs, such as warfarin.
Anticonvulsants
 
carbamazepine
 
Carbamazepine: In vivo studies have demonstrated an increase in plasma carbamazepine concentrations in subjects concomitantly receiving ketoconazole. Although there are no data regarding the effect of itraconazole on carbamazepine metabolism, because of the similarities between ketoconazole and itraconazole, concomitant administration of itraconazole and carbamazepine may inhibit the metabolism of carbamazepine. See also under ‘Drugs that may decrease itraconazole plasma concentrations’.
Antidiabetics
 
 
repaglinide,
saxagliptin
 
Antihelmintics and Antiprotozoals
 
 
praziquantel
 
Antimigraine Drugs
 
ergot alkaloids, such as dihydroergotamine, ergometrine (ergonovine), ergotamine, methylergometrine (methylergonovine)
 
 
eletriptan
Ergot Alkaloids: The potential increase in plasma concentrations of ergot alkaloids when coadministered with itraconazole may increase the risk of ergotism, i.e., a risk for vasospasm potentially leading to cerebral ischemia and/or ischemia of the extremities.
Antineoplastics
irinotecan
axitinib,
dabrafenib,
dasatinib,
ibrutinib,
nilotinib,
sunitinib
trabectedin
 
bortezomib,
busulphan,
docetaxel,
erlotinib,
gefitinib,
imatinib,
ixabepilone,
lapatinib,
ponatinib,
trimetrexate,
vinca alkaloids
Irinotecan: The potential increase in plasma concentrations of irinotecan when coadministered with itraconazole may increase the risk of potentially fatal adverse events.
 
Antipsychotics,
Anxiolytics and Hypnotics
lurasidone,
oral midazolam,
pimozide,
triazolam
 
alprazolam,
aripiprazole,
buspirone,
diazepam,
haloperidol,
midazolam IV,
perospirone,
quetiapine,
ramelteon,
risperidone
Midazolam, triazolam:  
Coadministration of itraconazole and oral midazolam, or triazolam may cause several-fold increases in plasma concentrations of these drugs. This may potentiate and prolong hypnotic and sedative effects, especially with repeated dosing or chronic administration of these agents.
Pimozide: The potential increase in plasma concentrations of pimozide when coadministered with itraconazole may increase the risk of serious cardiovascular events including QTc prolongation and torsade de pointes.
Antivirals
 
 
simeprevir
 
maraviroc,
indinavir,
ritonavir,
saquinavir
Indinavir, ritonavir: See also under ‘Drugs that may increase itraconazole plasma concentrations’.
Beta Blockers
 
 
nadolol
 
Calcium Channel
Blockers
felodipine,
nisoldipine
 
other dihydropyridines,
verapamil
 
Calcium channel blockers canhave a negative inotropic effect which may be additive to those of itraconazole. The potential increase in plasma concentrations of calcium channel blockers when co-administered with itraconazole may increase the risk of congestive heart failure.
Dihydropyridines: Concomitant administration of itraconazole may cause several-fold increases in plasma concentrations of dihydropyridines. Edema has been reported in patients concomitantly receiving itraconazole and dihydropyridine calcium channel blockers.
Cardiovascular Drugs, Miscellaneous
Ivabradine
ranolazine
aliskiren,
sildenafil, for the treatment of pulmonary hypertension
bosentan,
riociguat
Ivabradine: The potential increase in plasma concentrations of ivabradine when administered with itraconazole may increase the risk of ivabradine-related adverse events, such as atrial fibrillation, bradycardia, sinus arrest and heart block.
Ranolazine:
The potential increase in plasma concentrations of ranolazine when coadministered with itraconazole may increase the risk of serious cardiovascular events including QTc prolongation.
 
Diuretics
eplerenone
 
 
Eplerenone: The potential increase in plasma concentrations of eplerenone when coadministered with itraconazole may increase the risk of hyperkalemia and hypotension.
Gastrointestinal Drugs
cisapride
 
aprepitant
 
Cisapride: The potential increase in plasma concentrations of cisapride when coadministered with itraconazole may increase the risk of serious cardiovascular events including QTc prolongation.
 
 
 
 
 
Immunosuppres
sants
 
everolimus,
temsirolimus
budesonide,
ciclesonide,
cyclosporine,
dexamethasone,
fluticasone, methylprednisolone,
rapamycin (also known as sirolimus),
tacrolimus
 
Lipid Regulating Drugs
lovastatin,
simvastatin
 
atorvastatin
The potential increase in plasma concentrations of atorvastatin, lovastatin, and simvastatin when coadministered with itraconazole may increase the risk of skeletal muscle toxicity, including rhabdomyolysis.
Respiratory Drugs  
 
salmeterol  
 
 
Urological Drugs
fesoterodine, in subjects with moderate to severe renal impairment, or moderate to severe hepatic impairment, solifenacin, in subjects with severe renal impairment or moderate to severe hepatic impairment
darifenacin,
vardenafil
fesoterodine.
oxybutynin,
sildenafil, for the treatment of erectile dysfunction,
solifenacin,
tadalafil,
tolterodine
Fesoterodine: The potential increase in plasma concentrations of the fesoterodine active metabolite may be greater in subjects with moderate to severe renal impairment, or moderate to severe hepatic impairment, which may lead to an increased risk of adverse reactions.
Solifenacin: The potential increase in plasma concentrations of solifenacin in subjects with severe renal impairment or moderate to severe hepatic impairment, when coadministered with itraconazole may increase the risk of serious cardiovascular events including QT prolongation.
Other
colchicine, in subjects with renal or hepatic impairment
colchicine, conivaptan, tolvaptan
cinacalcet
Colchicine: The potential increase in plasma concentrations of colchicine when coadministered with itraconazole may increase the risk of potentially fatal adverse events.
Conivaptan and Tolvaptan: A safe and effective dose of either conivaptan or tolvaptan has not been established when coadministered with itraconazole.


Table name:
Bleeding times
Clinical Impact: Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention: This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact: The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention: Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact: Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention: This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.


Table name:
Table 3 Clinically Significant Drug Interactions with Meloxicam
Drugs  that  Interfere  with  Hemostasis 
Clinical  Impact
Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. 
Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. 
Intervention

Monitor patients with concomitant use of Meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin 
Clinical  Impact
Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].
Intervention

Concomitant use of Meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. Meloxicam is not a substitute for low dose aspirin for cardiovascular protection.
ACE  Inhibitors Angiotensin  Receptor  Blockers or  Beta - Blockers 
Clinical  Impact
NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). 
In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, coadministration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. 
Intervention

During concomitant use of Meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.  During concomitant use of Meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics 
Clinical  Impact
Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. 
Intervention

During concomitant use of Meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Lithium 
Clinical  Impact
NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [see Clinical Pharmacology (12.3)].
Intervention

During concomitant use of Meloxicam and lithium, monitor patients for signs of lithium toxicity. 
Methotrexate 
Clinical  Impact
Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). 
Intervention

During concomitant use of Meloxicam and methotrexate, monitor patients for methotrexate toxicity. 
Cyclosporine 
Clinical  Impact
Concomitant use of Meloxicam and cyclosporine may increase cyclosporine's nephrotoxicity. 
Intervention

During concomitant use of Meloxicam and cyclosporine, monitor patients for signs of worsening renal function. 
NSAIDs  and  Salicylates 
Clinical  Impact
Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention

The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended. 
Pemetrexed 
Clinical  Impact
Concomitant use of Meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). 
Intervention

During concomitant use of Meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. 

Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. 

In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended. 


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
   Effect on  
   Concentration of  
   Lamotrigine or  
 Concomitant Drug  Concomitant Drug  Clinical Comment
 Estrogen-containing oral  ↓ lamotrigine  Decreased lamotrigine concentrations
 contraceptive    approximately 50%.
 preparations containing    
 30 mcg ethinylestradiol  ↓ levonorgestrel  Decrease in levonorgestrel
 and 150 mcg    component by 19%.
 levonorgestrel    
 Carbamazepine  ↓ lamotrigine  Addition of carbamazepine decreases
 and carbamazepine epoxide    lamotrigine concentration
     approximately 40%.
     
   ? carbamazepine epoxide  May increase carbamazepine epoxide levels. 
 Lopinavir/ritonavir  ↓ lamotrigine  Decreased lamotrigine concentration
     approximately 50%.
 Atazanavir/ritonavir  ↓ lamotrigine  Decreased lamotrigine AUC
     approximately 32%.
 Phenobarbital/primidone  ↓ lamotrigine  Decreased lamotrigine concentration
     approximately 40%.
 Phenytoin  ↓ lamotrigine  Decreased lamotrigine concentration
     approximately 40%.
 Rifampin  ↓ lamotrigine  Decreased lamotrigine AUC
     approximately 40%.
 Valproate  ↑ lamotrigine  Increased lamotrigine concentrations
     slightly more than 2-fold.
     There are conflicting study results
   ? valproate  regarding effect of lamotrigine on
     valproate concentrations: 1) a mean 25%
     decrease in valproate concentrations in
     healthy volunteers, 2) no change in
     valproate concentrations in controlled
     clinical trials in patients with epilepsy.
 ↓ = Decreased (induces lamotrigine glucuronidation).
 ↑ = Increased (inhibits lamotrigine glucuronidation).
 ? = Conflicting data.


Table name:
Interacting Agents 
Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistatcontaining products), gemfibrozil, cyclosporine, danazol
 Contraindicated with simvastatin 
Verapamil, diltiazem, dronedarone
Do not exceed 10 mg simvastatin daily 
Amiodarone, amlodipine, ranolazine
Do not exceed 20 mg simvastatin daily 
Lomitapide
For patients with HoFH, do not exceed 
20 mg simvastatin dailyFor patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice 
Avoid grapefruit juice  


Table name:
Inhibitors of CYP3A4 and CYP2D6
Clinical Impact: The concomitant use of Oxycodone Hydrochloride Capsules and CYP3A4 inhibitors can increase the plasma concentration of oxycodone, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of Oxycodone Hydrochloride Capsules and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of Oxycodone Hydrochloride Capsules is achieved [see Warnings and Precautions ( 5.4 ) ]. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the oxycodone plasma concentration will decrease [see Clinical Pharmacology ( 12.3 )], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to oxycodone.
Intervention: If concomitant use is necessary, consider dosage reduction of Oxycodone Hydrochloride Capsules until stable drug effects are achieved.Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the Oxycodone Hydrochloride Capsules dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
Examples Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)
CYP3A4 Inducers
  Clinical Impact: The concomitant use of Oxycodone Hydrochloride Capsules and CYP3A4 inducers can decrease the plasma concentration of oxycodone [see Clinical Pharmacology ( 12.3 ) ], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to oxycodone [see Warnings and Precautions ( 5.4 ) ].
After stopping a CYP3A4 inducer, as the effects of the inducer decline, the oxycodone plasma concentration will increase [see Clinical Pharmacology ( 12.3 )], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.
Intervention: If concomitant use is necessary, consider increasing the Oxycodone Hydrochloride Capsule dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider Oxycodone Hydrochloride Capsule dosage reduction and monitor for signs of respiratory depression. 
Examples Rifampin, carbamazepine, phenytoin
Benzodiazepines and other Central Nervous System (CNS) Depressants
Clinical
Impact:
Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death. 
Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions ( 5.5 )].
Examples Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. 
Serotonergic Drugs
Clinical
Impact:
The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin. 
Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Oxycodone Hydrochloride Capsules if serotonin syndrome is suspected.
Examples Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). 
Monoamine Oxidase Inhibitors (MAOIs)
  Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions ( 5.2 )]. 
Intervention:  The use of Oxycodone Capsules is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
Examples phenelzine, tranylcypromine, linezolid 
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
  Clinical Impact: May reduce the analgesic effect of Oxycodone Hydrochloride Capsules and/or precipitate withdrawal symptoms. 
Intervention: Avoid concomitant use. 
Examples butorphanol, nalbuphine, pentazocine, buprenorphine 
Muscle Relaxants
Clinical
Impact:
Oxycodone may enhance the neuromuscular blocking action ofskeletal muscle relaxants and produce an increased degree of respiratory depression.  
Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Oxycodone Hydrochloride Capsules and/or the muscle relaxant as necessary. 
Diuretics
Clinical
Impact:
Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. 
Anticholinergic Drugs
Clinical
Impact:
The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. 
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when Oxycodone Hydrochloride Capsules is used concomitantly with anticholinergic drugs. 


Table name:
 Interacting Agents  Prescribing Recommendations
 Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)  Avoid atorvastatin
 HIV protease inhibitor (lopinavir plus ritonavir)  Use with caution and lowest dose necessary
 Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)  Do not exceed 20 mg atorvastatin daily
 HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
 Do not exceed 40 mg atorvastatin daily


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ Lamotrigine Decreased Lamotrigine levels approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide ↓ Lamotrigine Addition of carbamazepine decreases Lamotrigine concentration approximately 40%
? carbamazepine epoxide May increase CBZ epoxide levels.
Lopinavir/ritonavir ↓ Lamotrigine Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir ↓ Lamotrigine  Decreased lamotrigine AUC approximately 32%.
Phenobarbital/Primidone ↓ Lamotrigine Decreased Lamotrigine concentration approximately 40%
Phenytoin ↓ Lamotrigine Decreased Lamotrigine concentration approximately 40%
Rifampin ↓ Lamotrigine Decreased Lamotrigine AUC approximately 40%.
Valproate ↑ Lamotrigine Increased Lamotrigine concentrations slightly more than 2-fold.
? valproate There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.


Table name:
 Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
 Interacting Agents  Prescribing Recommendations
 Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)  Avoid atorvastatin
 HIV protease inhibitor (lopinavir plus ritonavir)  Use with caution and lowest dose necessary
 Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)  Do not exceed 20 mg atorvastatin daily
 HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
 Do not exceed 40 mg atorvastatin daily


Table name:
aDrugs That May Increase Tacrolimus Blood Concentrations
  a) This table is not all inclusive.
  b) In a study of 6 normal volunteers, a significant increase in tacrolimus oral bioavailability (14±5% vs. 30±8%) was observed with concomitant ketoconazole administration (200 mg). The apparent oral clearance of tacrolimus during ketoconazole administration was significantly decreased compared to tacrolimus alone (0.430±0.129 L/hr/kg vs. 0.148±0.043 L/hr/kg). Overall, IV clearance of tacrolimus was not significantly changed by ketoconazole coadministration, although it was highly variable between patients.
  c) Lansoprazole (CYP2C19, CYP3A4 substrate) may potentially inhibit CYP3A4-mediated metabolism of tacrolimus and thereby substantially increase tacrolimus whole blood concentrations, especially in transplant patients who are intermediate or poor CYP2C19 metabolizers, as compared to those patients who are efficient CYP2C19 metabolizers.
 Calcium  Antifungal  Macrolide
 Channel Blockers  Agents  Antibiotics
 diltiazem  clotrimazole  clarithromycin
 nicardipine  fluconazole  erythromycin
 nifedipine  itraconazole  troleandomycin
 verapamil  ketoconazoleb
 voriconazole
 Gastrointestinal  Other  
 Prokinetic Agents  Drugs  
 cisapride  bromocriptine  
 metoclopramide  chloramphenicol  
   cimetidine  
   cyclosporine  
   danazol  
   ethinyl estradiol  
   methylprednisolone  
   lansoprazolec  
   omeprazole  
   protease inhibitors  
   nefazodone  
   magnesium-aluminum-hydroxide  


Table name:
Table 25:  Clinically Important Drug Interactions with Aripiprazole:
Concomitant Drug Name or Drug Class
Clinical Rationale
Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine)
The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3) ].
With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION(2.7) ] .
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)
The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3) ] .
With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see DOSAGE AND ADMINISTRATION(2.7) ] .
Antihypertensive Drugs
Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.
Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.8) ] .
Benzodiazepines (e.g., lorazepam)
The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepamalone [see WARNINGS AND PRECAUTIONS (5.8 )]
Monitor sedation and blood pressure. Adjust dose accordingly.


Table name:
Digoxin concentrations increased greater than 50%
Digoxin Serum Concentration Increase Digoxin AUC Increase Recommendations
Amiodarone 70% NA Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30% to 50% or by modifying the dosing frequency and continue monitoring.
Captopril 58% 39%
Clarithromycin NA 70%
Dronedarone NA 150%
Gentamicin 129 to 212% NA
Erthromycin 100% NA
Itraconazole 60% NA
Lapatinib NA 180%
Propafenone NA 60 to 270 %
Quinidine 100% NA
Ranolazine 50% NA
Ritonavir NA 86%
Telaprevir 50% 85%
Tetracycline 100% NA
Verapamil 50 to 75% NA
Digoxin concentrations increased less than 50%
Atorvastatin 22% 15% Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15% to 30% or by modifying the dosing frequency and continue monitoring.
Carvedilol 16% 14%
Conivaptan 33% 43%
Diltiazem 20% NA
Indomethacin 40% NA
Nefazodone 27% 15%
Nifedipine 45% NA
Propantheline 24% 24%
Quinine NA 33%
Rabeprazole 29% 19%
Saquinavir 27% 49%
Spironolactone 25% NA
Telmisartan 20 to 49% NA
Ticagrelor 31% 28%
Tolvaptan 30% 20%
Trimethoprim 22 to28% NA
Digoxin concentrations increased, but magnitude is unclear
Alprazolam, azithromycin, cyclosporine, diclofenac, diphenoxylate, epoprostenol, esomeprazole, ibuprofen, ketoconazole, lansoprazole, metformin, omeprazole Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin concentrations decreased
Acarbose, activated charcoal, albuterol, antacids, certain cancer chemotherapy or radiation therapy, cholestyramine, colestipol, extenatide, kaolin-pectin, meals high in bran, metoclopramide, miglitol, neomycin, penicillamine, phenytoin, rifampin, St. John’s Wort, sucralfate, and sulfasalazine Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20 % to 40 % as necessary.


Table name:
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)   Avoid atorvastatin  
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Do not exceed 40 mg atorvastatin daily


Table name:
Table II. Clinically significant drug interactions with theophylline*.
Drug Type of Interaction Effect**
*Refer to PRECAUTIONS, Drug Interactions for further information regarding table.
**Average effect on steady state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.
Adenosine Theophylline blocks adenosine receptors. Higher doses of adenosine may be required to achieve desired effect.
Alcohol A single large dose of alcohol (3 ml/kg of whiskey) decreases theophylline clearance for up to 24 hours. 30% increase
Allopurinol Decreases theophylline clearance at allopurinol doses >600 mg/day. 25% increase
Amino glutethimide Increases theophylline clearance by induction of microsomal enzyme activity. 25% decrease
Carbamazepine Similar to aminoglutethimide. 30% decrease
Cimetidine Decreases theophylline clearance by inhibiting cytochrome P450 1A2. 70% increase
Ciprofloxacin Similar to cimetidine. 40% increase
Clarithromycin Similar to erythromycin. 25% increase
Diazepam Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram Decreases theophylline clearance by inhibiting hydroxylation and demethylation. 50% increase
Enoxacin Similar to cimetidine. 300% increase
Ephedrine Synergistic CNS effects Increased frequency of nausea, nervousness, and insomnia.
Erythromycin Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3. 35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen Estrogen containing oral contraceptives decrease theophylline clearance in a dose- dependent fashion. The effect of progesterone on theophylline clearance is unknown. 30% increase
Flurazepam Similar to diazepam. Similar to diazepam.
Fluvoxamine Similar to cimetidine Similar to cimetidine
Halothane Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines. Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-A Decreases theophylline clearance. 100% increase
Isoproterenol (IV) Increases theophylline clearance. 20% decrease
Ketamine Pharmacologic May lower theophylline seizure threshold.
Lithium Theophylline increases renal lithium clearance. Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam Similar to diazepam. Similar to diazepam.
Methotrexate (MTX) Decreases theophylline clearance. 20% increase after low dose MTX, higher dose MTX may have a greater effect.
Mexiletine Similar to disulfiram. 80% increase
Midazolam Similar to diazepam. Similar to diazepam.
Moricizine Increases theophylline clearance. 25% decrease
Pancuronium Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition. Larger dose of pancuronium may be required to achieve neuromuscular blockade.
Pentoxifylline Decreases theophylline clearance. 30% increase
Phenobarbital (PB) Similar to aminoglutethimide. 25% decrease after two weeks of concurrent PB.
Phenytoin Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption. Serum theophylline and phenytoin concentrations decrease about 40%.
Propafenone Decreases theophylline clearance and pharmacologic interaction. 40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Propranolol Similar to cimetidine and pharmacologic interaction. 100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Rifampin Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity. 20-40% decrease
Sulfinpyrazone Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline. 20% decrease
Tacrine Similar to cimetidine, also increases renal clearance of theophylline. 90% increase
Thiabendazole Decreases theophylline clearance. 190% increase
Ticlopidine Decreases theophylline clearance. 60% increase
Troleandomycin Similar to erythromycin. 33-100% increase depending on troleandomycin dose.
Verapamil Similar to disulfiram. 20% increase


Table name:

Figure 7: Mean Standing Systolic Blood Pressure Change from Baseline


Table name:
Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
 * Change relative to reference
 Coadministered Drug
 Dosing Schedule
 Effect on Active
Moiety (Risperidone + 9-
Hydroxy- Risperidone (Ratio*)
 Risperidone Dose
Recommendation
 
 Coadministered Drug
 Risperidone
 AUC
 Cmax
 
 Enzyme (CYP2D6)
Inhibitors
 
 
 
 
 
 Fluoxetine
 20 mg/day 
 2 or 3 mg twice
daily
 1.4 
 1.5
 Re-evaluate dosing. Do not exceed 8 mg/day
 Paroxetine
 10 mg/day 
 4 mg/day
 1.3
 -
 Re-evaluate dosing. 
 
 20 mg/day 
 4 mg/day
 1.6
 -
 Do not exceed 8 mg/day
 
 40 mg/day 
 4 mg/day
 1.8
 -
 
 Enzyme (CYP3A/ PgP inducers) Inducers
 
 
 
 
 
 Carbamazepine 
 573 ± 168 mg/day
 3 mg twice daily
 0.51 
 0.55
 Titrate dose upwards.
Do not exceed twice the patient’s usual dose
 Enzyme (CYP3A)
Inhibitors
 
 
 
 
 
 Ranitidine 
 150 mg twice daily
 1 mg single dose
 1.2 
 1.4
 Dose adjustment not
needed
 Cimetidine 
 400 mg twice daily
 1 mg single dose
 1.1 
 1.3
 Dose adjustment not
needed
 Erythromycin 

 500 mg four times
daily
 1 mg single dose
 1.1 
 0.94
 Dose adjustment not
needed
 
 
 
 
 
 
 Other Drugs
 
 
 
 
 
 Amitriptyline 
 50 mg twice daily
 3 mg twice daily
 1.2 
 1.1
 Dose adjustment not
needed


Table name:
Table 4. Mean (95% C.I.) maximal change in baseline in systolic blood pressure (mmHg) following vardenafil 10 and 20 mg in healthy volunteers on daily alpha-blocker therapy
Dosing of Vardenafil and Alpha-Blocker
Separated by 6 Hours
Simultaneous dosing of Vardenafil
and Alpha-Blocker
Alpha-Blocker Vardenafil 10 mg
Placebo-Subtracted
Vardenafil 20 mg
Placebo-Subtracted
Vardenafil 10 mg
Placebo-Subtracted
Vardenafil 20 mg
Placebo-Subtracted
Terazosin
10 mg daily
Standing SBP -7 (-10, -3) -11 (-14, -7) -23 (-31, 16) Due to the sample size, confidence intervals may not be an accurate measure for these data. These values represent the range for the difference. -14 (-33, 11)
Supine SBP -5 (-8, -2) -7 (-11, -4) -7 (-25, 19) -7 (-31, 22)
Tamsulosin
0.4 mg daily
Standing SBP -4 (-8, -1) -8 (-11, -4) -8 (-14, -2) -8 (-14, -1)
Supine SBP -4 (-8, 0) -7 (-11, -3) -5 (-9, -2) -3 (-7, 0)


Table name:
Table 13 Established and Other Potentially Significant Drug Interactions
 Concomitant  Drug
 Effect  on  Concentration  of  Lamotrigine  or  Concomitant  Drug
 Clinical  Comment
 ↓ = Decreased (induces lamotrigine glucuronidation).
 ↑ = Increased (inhibits lamotrigine glucuronidation).
 ? = Conflicting data.
 Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel
 ↓ lamotrigine
 Decreased lamotrigine concentrations approximately 50%.
 
 ↓ levonorgestrel
 Decrease in levonorgestrel component by 19%.
 Carbamazepine and epoxide
 ↓ lamotrigine
 Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
 
 ? Carbamazepine 
 epoxide
 May increase 
Carbamazepine epoxide levels.
 Lopinavir/ritonavir 
 ↓ lamotrigine 
 Decreased lamotrigine concentration approximately 50%. 
 Atazanavir/ritonavir 
 ↓ lamotrigine 
 Decreased lamotrigine AUC approximately 32%. 
 Phenobarbital/Primidone
 ↓ lamotrigine
 Decreased lamotrigine concentration approximately 40%.
 Phenytoin
 ↓ lamotrigine
 Decreased lamotrigine concentration approximately 40%.
 Rifampin
 ↓ lamotrigine
 Decreased lamotrigine AUC approximately 40%.
 Valproate
 ↑ lamotrigine
 Increased lamotrigine concentrations slightly more than 2-fold.
 
 ? valproate
 There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy. 


Table name:
Table 3: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction [See Clinical Pharmacology (12.3)]
Concomitant Drug Class:
Drug Name
Effect on Concentration of Etravirine or Concomitant Drug Clinical Comment
↑ = increase, ↓ = decrease, ↔ = no change
HIV-Antiviral Agents: Integrase Strand Inhibitors
dolutegravirThe interaction between INTELENCE® and the drug was evaluated in a clinical study. All other drug interactions shown are predicted. ↓ dolutegravir
↔ etravirine
Etravirine significantly reduced plasma concentrations of dolutegravir. Using cross-study comparisons to historical pharmacokinetic data for etravirine, dolutegravir did not appear to affect the pharmacokinetics of etravirine.
dolutegravir/darunavir/ritonavir ↓ dolutegravir
↔ etravirine
The effect of etravirine on dolutegravir plasma concentrations was mitigated by co-administration of darunavir/ritonavir or lopinavir/ritonavir, and is expected to be mitigated by atazanavir/ritonavir. Dolutegravir should only be used with INTELENCE® when co-administered with atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir.
dolutegravir/lopinavir/ritonavir ↔ dolutegravir
↔ etravirine
HIV-Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
efavirenz
nevirapine
↓ etravirine Combining two NNRTIs has not been shown to be beneficial. Concomitant use of INTELENCE® with efavirenz or nevirapine may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of INTELENCE®. INTELENCE® and other NNRTIs should not be co-administered.
delavirdine ↑ etravirine Combining two NNRTIs has not been shown to be beneficial. INTELENCE® and delavirdine should not be co-administered.
rilpivirine ↓ rilpivirine
↔ etravirine
Combining two NNRTIs has not been shown to be beneficial. INTELENCE® and rilpivirine should not be coadministered.
HIV-Antiviral Agents: Protease Inhibitors (PIs)
atazanavir
(without ritonavir)
↓ atazanavir INTELENCE® should not be co-administered with atazanavir without low-dose ritonavir.
atazanavir/ritonavir ↓ atazanavir
↔ etravirine
Concomitant use of INTELENCE® with atazanavir/ritonavir decreased atazanavir Cmin but it is not considered clinically relevant.. The mean systemic exposure (AUC) of etravirine after co-administration of INTELENCE® with atazanavir/ritonavir in HIV-infected patients was similar to the mean systemic exposure of etravirine observed in the Phase 3 trials after co-administration of INTELENCE® and darunavir/ritonavir (as part of the background regimen). INTELENCE® and atazanavir/ritonavir can be co-administered without dose adjustments.
darunavir/ritonavir ↓ etravirine The mean systemic exposure (AUC) of etravirine was reduced when INTELENCE® was co-administered with darunavir/ritonavir. Because all subjects in the Phase 3 trials received darunavir/ritonavir as part of the background regimen and etravirine exposures from these trials were determined to be safe and effective, INTELENCE® and darunavir/ritonavir can be co-administered without dose adjustments.
fosamprenavir
(without ritonavir)
↑ amprenavir Concomitant use of INTELENCE® with fosamprenavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of amprenavir. INTELENCE® should not be co-administered with fosamprenavir without low-dose ritonavir.
fosamprenavir/ritonavir ↑ amprenavir Due to a significant increase in the systemic exposure of amprenavir, the appropriate doses of the combination of INTELENCE® and fosamprenavir/ritonavir have not been established. INTELENCE® and fosamprenavir/ritonavir should not be co-administered.
indinavir
(without ritonavir)
↓ indinavir Concomitant use of INTELENCE® with indinavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of indinavir. INTELENCE® should not be co-administered with indinavir without low-dose ritonavir.
lopinavir/ritonavir ↓ etravirine The mean systemic exposure (AUC) of etravirine was reduced after co-administration of INTELENCE® with lopinavir/ritonavir (tablet). Because the reduction in the mean systemic exposures of etravirine in the presence of lopinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, INTELENCE® and lopinavir/ritonavir can be co-administered without dose adjustments.
nelfinavir
(without ritonavir)
↑ nelfinavir Concomitant use of INTELENCE® with nelfinavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of nelfinavir. INTELENCE® should not be co-administered with nelfinavir without low-dose ritonavir.
ritonavir ↓ etravirine Concomitant use of INTELENCE® with ritonavir 600 mg twice daily may cause a significant decrease in the plasma concentration of etravirine and loss of therapeutic effect of INTELENCE®. INTELENCE® and ritonavir 600 mg twice daily should not be co-administered.
saquinavir/ritonavir ↓ etravirine The mean systemic exposure (AUC) of etravirine was reduced when INTELENCE® was co-administered with saquinavir/ritonavir. Because the reduction in the mean systemic exposures of etravirine in the presence of saquinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, INTELENCE® and saquinavir/ritonavir can be co-administered without dose adjustments.
tipranavir/ritonavir ↓ etravirine Concomitant use of INTELENCE® with tipranavir/ritonavir may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of INTELENCE®. INTELENCE® and tipranavir/ritonavir should not be co-administered.
CCR5 Antagonists
maraviroc ↔ etravirine
↓ maraviroc
When INTELENCE® is co-administered with maraviroc in the absence of a potent CYP3A inhibitor (e.g., ritonavir boosted protease inhibitor), the recommended dose of maraviroc is 600 mg twice daily. No dose adjustment of INTELENCE® is needed.
maraviroc/darunavir/ritonavir The reference for etravirine exposure is the pharmacokinetic parameters of etravirine in the presence of darunavir/ritonavir ↔ etravirine
↑ maraviroc
When INTELENCE® is co-administered with maraviroc in the presence of a potent CYP3A inhibitor (e.g., ritonavir boosted protease inhibitor), the recommended dose of maraviroc is 150 mg twice daily. No dose adjustment of INTELENCE® is needed.
Other Agents
Antiarrhythmics:
digoxin
↔ etravirine
↑ digoxin
For patients who are initiating a combination of INTELENCE® and digoxin, the lowest dose of digoxin should initially be prescribed. For patients on a stable digoxin regimen and initiating INTELENCE®, no dose adjustment of either INTELENCE® or digoxin is needed. The serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect.
amiodarone,
bepridil,
disopyramide,
flecainide,
lidocaine (systemic),
mexiletine,
propafenone,
quinidine
↓ antiarrhythmics Concentrations of these antiarrhythmics may be decreased when co-administered with INTELENCE®. INTELENCE® and antiarrhythmics should be co-administered with caution. Drug concentration monitoring is recommended, if available.
Anticoagulants:
warfarin
↑ anticoagulants Warfarin concentrations may be increased when co-administered with INTELENCE®. The international normalized ratio (INR) should be monitored when warfarin is combined with INTELENCE®.
Anticonvulsants:
carbamazepine,
phenobarbital,
phenytoin
↓ etravirine Carbamazepine, phenobarbital and phenytoin are inducers of CYP450 enzymes. INTELENCE® should not be used in combination with carbamazepine, phenobarbital, or phenytoin as co-administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE®.
Antifungals:
fluconazole,
voriconazole
↑ etravirine
↔ fluconazole
↑ voriconazole
Co-administration of etravirine and fluconazole significantly increased etravirine exposures. The amount of safety data at these increased etravirine exposures is limited, therefore, etravirine and fluconazole should be co-administered with caution. No dose adjustment of INTELENCE® or fluconazole is needed.
Co-administration of etravirine and voriconazole significantly increased etravirine exposures. The amount of safety data at these increased etravirine exposures is limited, therefore, etravirine and voriconazole should be co-administered with caution. No dose adjustment of INTELENCE® or voriconazole is needed.
Antifungals:
itraconazole,
ketoconazole,
posaconazole
↑ etravirine
↓ itraconazole
↓ ketoconazole
↔ posaconazole
Posaconazole, a potent inhibitor of CYP3A4, may increase plasma concentrations of etravirine. Itraconazole and ketoconazole are potent inhibitors as well as substrates of CYP3A4. Concomitant systemic use of itraconazole or ketoconazole and INTELENCE® may increase plasma concentrations of etravirine. Simultaneously, plasma concentrations of itraconazole or ketoconazole may be decreased by INTELENCE®. Dose adjustments for itraconazole, ketoconazole or posaconazole may be necessary depending on the other co-administered drugs.
Antiinfectives:
clarithromycin
↑ etravirine
↓ clarithromycin
↑ 14-OH-clarithromycin
Clarithromycin exposure was decreased by INTELENCE®; however, concentrations of the active metabolite, 14-hydroxy-clarithromycin, were increased. Because 14-hydroxy-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered for the treatment of MAC.
Antimalarials:
artemether/lumefantrine
↔ etravirine
↓ artemether
↓ dihydroartemisinin
↓ lumefantrine
Caution is warranted when co-administering INTELENCE® and artemether/lumefantrine as it is unknown whether the decrease in exposure of artemether or its active metabolite, dihydroartemisinin, could result in decreased antimalarial efficacy. No dose adjustment is needed for INTELENCE®.
Antimycobacterials:
rifampin,
rifapentine
↓ etravirine Rifampin and rifapentine are potent inducers of CYP450 enzymes. INTELENCE® should not be used with rifampin or rifapentine as co-administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE®.
Antimycobacterials:
rifabutin
↓ etravirine
↓ rifabutin
↓ 25-O-desacetylrifabutin
If INTELENCE® is NOT co-administered with a protease inhibitor/ritonavir, then rifabutin at a dose of 300 mg once daily is recommended.
If INTELENCE® is co-administered with darunavir/ritonavir, lopinavir/ritonavir or saquinavir/ritonavir, then rifabutin should not be co-administered due to the potential for significant reductions in etravirine exposure.
Benzodiazepines:
diazepam
↑ diazepam Concomitant use of INTELENCE® with diazepam may increase plasma concentrations of diazepam. A decrease in diazepam dose may be needed.
Corticosteroids:
dexamethasone (systemic)
↓ etravirine Systemic dexamethasone induces CYP3A and can decrease etravirine plasma concentrations. This may result in loss of therapeutic effect of INTELENCE®. Systemic dexamethasone should be used with caution or alternatives should be considered, particularly for long-term use.
Herbal Products:
St. John's wort (Hypericum perforatum)
↓ etravirine Concomitant use of INTELENCE® with products containing St. John's wort may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE®. INTELENCE® and products containing St. John's wort should not be co-administered.
Hepatitis C Virus (HCV) Direct-Acting Antivirals:
boceprevir
↓etravirine
↑ boceprevir
The combination of INTELENCE® and boceprevir can be used without dose adjustments.
However, co-administration of INTELENCE® and boceprevir is not recommended in the presence of other drugs which may further decrease etravirine exposure. This includes, but is not limited to, darunavir/ritonavir, lopinavir/ritonavir, saquinavir/ritonavir, tenofovir disoproxil fumarate, or rifabutin.
telaprevir ↔ etravirine
↓ telaprevir
There are insufficient data to make a dosing recommendation for telaprevir when used with INTELENCE®.
HMG-CoA
Reductase Inhibitors:
atorvastatin

fluvastatin,
lovastatin,
pitavastatin,
pravastatin,
rosuvastatin,
simvastatin
↔ etravirine
↓ atorvastatin
↑ 2-OH-atorvastatin

↔ etravirine
↑ fluvastatin,
↓ lovastatin,
↑ pitavastatin,
↔ pravastatin,
↔ rosuvastatin,
↓ simvastatin
The combination of INTELENCE® and atorvastatin can be given without dose adjustments, however, the dose of atorvastatin may need to be altered based on clinical response.

No interaction between pravastatin, rosuvastatin and INTELENCE® is expected.

Lovastatin and simvastatin are CYP3A substrates and co-administration with INTELENCE® may result in lower plasma concentrations of the HMG-CoA reductase inhibitor. Fluvastatin and pitavastatin are metabolized by CYP2C9 and co-administration with INTELENCE® may result in higher plasma concentrations of the HMG-CoA reductase inhibitor. Dose adjustments for these HMG-CoA reductase inhibitors may be necessary.
Immunosuppressants:
cyclosporine,
sirolimus,
tacrolimus
↓ immunosuppressant INTELENCE® and systemic immunosuppressants should be co-administered with caution because plasma concentrations of cyclosporine, sirolimus, or tacrolimus may be affected.
Narcotic Analgesics/Treatment of Opioid Dependence:
buprenorphine, buprenorphine/naloxone,
methadone
↔ etravirine
↓ buprenorphine
↔ norbuprenorphine
↔ methadone
INTELENCE® and buprenorphine (or buprenorphine/naloxone) can be co-administered without dose adjustments, however, clinical monitoring for withdrawal symptoms is recommended as buprenorphine (or buprenorphine/naloxone) maintenance therapy may need to be adjusted in some patients.

INTELENCE® and methadone can be co-administered without dose adjustments, however, clinical monitoring for withdrawal symptoms is recommended as methadone maintenance therapy may need to be adjusted in some patients.
Phosphodiesterase Type 5
(PDE-5) Inhibitors:
sildenafil,
tadalafil,
vardenafil
↓ sildenafil
↓ N-desmethyl-sildenafil
INTELENCE® and sildenafil can be co-administered without dose adjustments, however, the dose of sildenafil may need to be altered based on clinical effect.
Platelet Aggregation Inhibitors:
clopidogrel
↓ clopidogrel (active) metabolite Activation of clopidogrel to its active metabolite may be decreased when clopidogrel is co-administered with INTELENCE®. Alternatives to clopidogrel should be considered.


Table name:
Table II. Clinically significant drug interactions with theophylline.*
Drug Type of Interaction Effect†
Adenosine Theophylline blocks adenosine receptors. Higher doses of adenosine may berequired to achieve desired effect.
Alcohol A single large dose of alcohol (3 mL/kg ofwhiskey) decreases theophylline clearance for up to24 hours 30% increase
Allopurinol Decreases theophylline clearance at allopurinoldoses  600 mg/day 25% increase
Aminoglutethimide Increases theophylline clearance by induction ofmicrosomal enzyme activity. 25% decrease
Carbamazepine Similar to aminoglutethimide. 30% decrease
Cimetidine Decreases theophylline clearance by inhibitingcytochrome P450 1A2 70% increase
Ciprofloxacin Similar to cimetidine. 40% increase
Clarithromycin Similar to erythromycin. 25% increase
Diazepam Benzodiazepines increase CNS concentratrionsof adenosine, a potent CNS depressant, whiletheophylline blocks adenosine receptors. Larger diazepam doses may be requiredto produce desired level of sedation.Discontinuation of theophylline withoutreduction of diazepam dose may resultin respiratory depression.
Disulfiram Decreases theophylline clearance by inhibitinghydroxylation and demethylation. 50% increase
Enoxacin Similar to cimetidine. 300% increase
Ephedrine Synergistic CNS effects Increased frequency of nausea,nervousness, and insomnia.
Erythromycin Erythromycin metabolite decreases theophyllineclearance by inhibiting cytochrome P450 3A3. 35% increase. Erythromycin steady-state serum concentrations decrease by asimilar amount.
Estrogen Estrogen containing oral contraceptives decreasetheophylline clearance in a dose-dependentfashion. The effect of progesterone on theophyllineclearance in unknown. 30% increase
Flurazepam Similar to diazepam. Similar to diazepam.
Fluvoxamine Similar to cimetidine. Similar to cimetidine.
Halothane Halothane sensitizes the myocardium tocatecholamines, theophylline increases release ofendogenous catecholamines. Increased risk of ventriculararrhythmias.
Interferon, human recombinant alpha-A Decreases theophylline clearance. 100% increase
Isoproterenol (IV) Increase theophylline clearance. 20% increase
Ketamine Pharmacologic May lower theophylline seizurethreshold.
Lithium Theophylline increases renal lithium clearance. Lithium dose required to achievea therapeutic serum concentrationincreased an average of 60%.
Lorazepam Similar to diazepam. Similar to diazepam.
Methotrexate (MTX) Decreases theophylline clearance. 20% increase after low dose MTX,higher dose MTX may have a greatereffect.
Mexiletine Similar to disulfiram. 80% increase
Midazolam Similar to diazepam. Similar to diazepam.
Moricizine Increases theophylline clearance. 25% increase
Pancuronium Theophylline may antagonize non-depolarizingneuromuscular blocking effects;possibly due tophosphodiesterase inhibition. Larger dose of pancuronium may berequired to achieve neuromuscularblockade.
Pentoxifylline Decreases theophylline clearance. 30% increase
Phenobarbital (PB) Similar to aminoglutethimide. 25% decrease after two weeks ofconcurrent PB.
Phenytoin Phenytoin increases theophylline clearance byincreasing microsomal enzyme activity. Serum theophylline and phenytoinconcentrations decrease about 40%.
Propafenone Decreases theophylline clearance andpharmacologic interaction. 40% increase. Beta-2 blocking effectmay decrease efficacy of theophylline.
Propranolol Similar to cimetidine and pharmacologicinteraction. 100% increase Beta-2 blocking effectmay decrease efficacy of theophylline
Rifampin Increases theophylline clearance by increasingcytochrome P450 1A2 and 3A3 activity. 20-40% decrease
Sulfinpyrazone Increase theophylline clearance by increasingdemethylation and hydroxylation. Decreases renalclearance of theophylline. 20% increase
Tacrine Similar to cimetidine, also increases renalclearance of theophylline. 90% increase
Thiabendazole Decreases theophylline clearance. 190% increase
Ticlopidine Decreases theophylline clearance. 60% increase
Troleandomycin Similar to erythromycin. 33-100% increase depending ontroleandomycin dose.
Verapamil Similar to disulfiram. 20% increase


Table name:
Drugs That Interfere with Hemostasis
Clinical Impact:
Indomethacin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of indomethacin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:
Monitor patients with concomitant use of indomethacin extended-release capsules with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11) ].
Aspirin
Clinical Impact:
Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2) ].
Intervention:
Concomitant use of indomethacin extended-release capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11) ].
Indomethacin extended-release capsules are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:
 NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).  In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:
During concomitant use of indomethacin extended-release capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of indomethacin extended-release capsules and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6) ]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:
Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
 
It has been reported that the addition of triamterene to a maintenance schedule of indomethacin extended-release capsules resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin extended-release capsules and triamterene should not be administered together.
 
Both indomethacin extended-release capsules and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin extended-release capsules and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently.
Intervention:
Indomethacin and triamterene should not be administered together. During concomitant use of indomethacin extended-release capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects.
Be aware that indomethacin and potassium-sparing diuretics may both be associated with increased serum potassium levels [see Warnings and Precautions (5.6) ].
Digoxin
Clinical Impact:
The concomitant use of indomethacin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:
During concomitant use of indomethacin extended-release capsules and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:
NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:
During concomitant use of indomethacin extended-release capsules and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:
Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:
During concomitant use of indomethacin extended-release capsules and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:
Concomitant use of indomethacin extended-release capsules and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:
During concomitant use of indomethacin extended-release capsules and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:
Concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)]. Combined use with diflunisal may be particularly hazardous because diflunisal causes significantly higher plasma levels of indomethacin. [see Clinical Pharmacology (12.3) ]. In some patients, combined use of indomethacin and diflunisal has been associated with fatal gastrointestinal hemorrhage.
Intervention:
The concomitant use of indomethacin with other NSAIDs or salicylates, especially diflunisal, is not recommended.
Pemetrexed
Clinical Impact:
Concomitant use of indomethacin extended-release capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:
During concomitant use of indomethacin extended-release capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.
 
NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.
 
In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Probenecid
Clinical Impact:
When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased.
Intervention:
During the concomitant use of indomethacin extended-release capsules and probenecid, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect. When increases in the dose of indomethacin are made, they should be made carefully and in small increments.


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.11, 7.3)


Table name:
Table 6: Predicted Drug Interactions with VIDEX EC
Drug or Drug Class Effect Clinical Comment
↑ Indicates increase.
a  Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that cause pancreatic toxicity is required, suspension of VIDEX EC is recommended [see Warnings and Precautions (5.1) ].
b  [See Warnings and Precautions (5.6) .]
Drugs that may cause pancreatic toxicity ↑ risk of pancreatitis Use only with extreme caution.a
Neurotoxic drugs ↑ risk of neuropathy Use with caution.b


Table name:
 Calcium Channel Blockers  Antifungals  Antibiotics  Glucocorticoids  Other Drugs
 diltiazem  fluconazole  azithromycin  methylprednisolone  allopurinol
 nicardipine  itraconazole  clarithromycin    amiodarone
 verapamil  ketoconazole  erythromycin    bromocriptine
   voriconazole  quinupristin/    colchicine
     dalfopristin    danazol
         imatinib
         metoclopramide
         nefazodone
         oral contraceptives


Table name:
AED Coadministered AED Concentration Topiramate Concentration
Phenytoin
NC or 25% increase Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
48% decrease


Carbamazepine (CBZ)
NC
40% decrease
CBZ epoxide Is not administered but is an active metabolite of carbamazepine.
NC
NE
Valproic acid
11% decrease
14% decrease
Phenobarbital
NC
NE
Primidone
NC
NE
Lamotrigine
NC at TPM doses up to 400 mg/day
13% decrease


Table name:
Table II. Clinically significant drug interactions with theophylline.Refer to PRECAUTIONS, Drug Interactions for further information regarding table.
Drug Type of Interaction EffectAverage effect on steady state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.
Adenosine Theophylline blocks adenosine receptors. Higher doses of adenosine may be required to achieve desired effect.
Alcohol A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours. 30% increase
Allopurinol Decreases theophylline clearance at allopurinol doses greater than or equal to 600 mg/day. 25% increase
Aminoglutethimide Increases theophylline clearance by induction of microsomal enzyme activity. 25% decrease
Carbamazepine Similar to aminoglutethimide. 30% decrease
Cimetidine Decreases theophylline clearance by inhibiting cytochrome P450 1A2. 70% increase
Ciprofloxacin Similar to cimetidine. 40% increase
Clarithromycin Similar to erythromycin. 25% increase
Diazepam Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram Decreases theophylline clearance by inhibiting hydroxylation and demethylation. 50% increase
Enoxacin Similar to cimetidine. 300% increase
Ephedrine Synergistic CNS effects. Increased frequency of nausea, nervousness, and insomnia.
Erythromycin Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3. 35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown. 30% increase
Flurazepam Similar to diazepam. Similar to diazepam.
Fluvoxamine Similar to cimetidine. Similar to cimetidine.
Halothane Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines. Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-A Decreases theophylline clearance. 100% increase
Isoproterenol (IV) Increases theophylline clearance. 20% decrease
Ketamine Pharmacologic May lower theophylline seizure threshold.
Lithium Theophylline increases renal lithium clearance. Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam Similar to diazepam. Similar to diazepam.
Methotrexate (MTX) Decreases theophylline clearance. 20% increase after low dose MTX, higher dose MTX may have a greater effect.
Mexiletine Similar to disulfiram. 80% increase
Midazolam Similar to diazepam. Similar to diazepam.
Moricizine Increases theophylline clearance. 25% decrease
Pancuronium Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition. Larger dose of pancuronium may be required to achieve neuromuscular blockade.
Pentoxifylline Decreases theophylline clearance. 30% increase
Phenobarbital (PB) Similar to aminoglutethimide. 25% decrease after two weeks of concurrent PB.
Phenytoin Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption. Serum theophylline and phenytoin concentrations decrease about 40%.
Propafenone Decreases theophylline clearance and pharmacologic interaction. 40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Propranolol Similar to cimetidine and pharmacologic interaction. 100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Rifampin Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity. 20–40% decrease
Sulfinpyrazone Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline. 20% decrease
Tacrine Similar to cimetidine, also increases renal clearance theophylline. 90% increase
Thiabendazole Decreases theophylline clearance. 190% increase
Ticlopidine Decreases theophylline clearance. 60% increase
Troleandomycin Similar to erythromycin. 33–100% increase depending on troleandomycin dose.
Verapamil Similar to disulfiram. 20% increase


Table name:
Interacting DrugInteracting Drug InteractionInteraction
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products.
Warfarin
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents
Carefully monitor blood glucose (5.11, 7.3)


Table name:
Factors Dosage Adjustments for REXULTI (2.5)
Strong CYP2D6* or CYP3A4 inhibitors Administer half of usual dose
Strong/moderate CYP2D6 with Strong/moderate CYP3A4 inhibitors Administer a quarter of usual dose
Known CYP2D6 Poor Metabolizers taking strong/moderate CYP3A4 inhibitors Administer a quarter of usual dose
Strong CYP3A4 inducers Double the usual dose and further adjust based on clinical response


Table name:
Drug Interactions Associated with Increased Risk of  Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice Avoid grapefruit juice


Table name:
AED Coadministered AED Concentration Topiramate Concentration
Phenytoin NC or 25% increase a 48% decrease
Carbamazepine (CBZ) NC 40% decrease
CBZ epoxide b NC NE
Valproic acid 11% decrease 14% decrease
Phenobarbital NC NE
Primidone NC NE
Lamotrigine NC at TPM doses up to 400 mg/day 13% decrease


Table name:
Table 3: Drug Interactions: Pharmacokinetic Parameters for Coadministered Drug in the Presence of Indinavir (See PRECAUTIONS, Table 9 for Recommended Alterations in Dose or Regimen)
Coadministered drug Dose of Coadministered drug (mg) Dose of CRIXIVAN (mg) n Ratio (with/without CRIXIVAN) of Coadministered Drug
Pharmacokinetic Parameters
(90% CI); No Effect = 1.00
Cmax AUC Cmin
All interaction studies conducted in healthy, HIV-negative adult subjects, unless otherwise indicated.
Clarithromycin 500 twice daily,
7 days
800 three times daily, 7 days 12 1.19
(1.02, 1.39)
1.47
(1.30, 1.65)
1.97
(1.58, 2.46)
n=11
Efavirenz 200 once daily,
14 days
800 three times daily, 14 days 20 No significant change No significant change --
Ethinyl Estradiol
(ORTHO-NOVUM 1/35)Registered trademark of Ortho Pharmaceutical Corporation.
35 mcg, 8 days 800 three times daily, 8 days 18 1.02
(0.96, 1.09)
1.22
(1.15, 1.30)
1.37
(1.24, 1.51)
Isoniazid 300 once daily in the morning,
8 days
800 three times daily, 8 days 11 1.34
(1.12, 1.60)
1.12
(1.03, 1.22)
1.00
(0.92, 1.08)
MethadoneStudy conducted in subjects on methadone maintenance. 20-60 once daily in the morning,
8 days
800 three times daily, 8 days 12 0.93
(0.84, 1.03)
0.96
(0.86, 1.06)
1.06
(0.94, 1.19)
Norethindrone
(ORTHO-NOVUM 1/35)
1 mcg, 8 days 800 three times daily, 8 days 18 1.05
(0.95, 1.16)
1.26
(1.20, 1.31)
1.44
(1.32, 1.57)
Rifabutin
150 mg once daily in the morning, 11 days + indinavir compared to 300 mg once daily in the morning, 11 days alone
150 once daily in the morning,
10 days

300 once daily in the morning,
10 days
800 three times daily, 10 days


800 three times daily, 10 days
14



10
1.29
(1.05, 1.59)


2.34
(1.64, 3.35)
1.54
(1.33, 1.79)


2.73
(1.99, 3.77)
1.99
(1.71, 2.31)
n=13

3.44
(2.65, 4.46)
n=9
Ritonavir 100 twice daily,
14 days
800 twice daily,
14 days
10, 4Parallel group design; n for coadministered drug + indinavir, n for coadministered drug alone. 1.61
(1.13, 2.29)
1.72
(1.20, 2.48)
1.62
(0.93, 2.85)
200 twice daily,
14 days
800 twice daily,
14 days
9, 5 1.19
(0.85, 1.66)
1.96
(1.39, 2.76)
4.71
(2.66, 8.33)
n=9, 4
Saquinavir
   Hard gel formulation 600 single dose 800 three times daily, 2 days 6 4.7
(2.7, 8.1)
6.0
(4.0, 9.1)
2.9
(1.7, 4.7)C6hr
   Soft gel formulation 800 single dose 800 three times daily, 2 days 6 6.5
(4.7, 9.1)
7.2
(4.3, 11.9)
5.5
(2.2, 14.1)
   Soft gel formulation 1200 single dose 800 three times daily, 2 days 6 4.0
(2.7, 5.9)
4.6
(3.2, 6.7)
5.5
(3.7, 8.3)
Sildenafil 25 single dose 800 three times daily 6 See text below for discussion of interaction.
StavudineStudy conducted in HIV-positive subjects. 40 twice daily,
7 days
800 three times daily, 7 days 13 0.86
(0.73, 1.03)
1.21
(1.09, 1.33)
Not Done
Theophylline 250 single dose (on Days 1 and 7) 800 three times daily, 6 days (Days 2 to 7) 12, 4 0.88
(0.76, 1.03)
1.14
(1.04, 1.24)
1.13
(0.86, 1.49)
n=7, 3
Trimethoprim/
Sulfamethoxazole
   Trimethoprim 800 Trimethoprim/
160 Sulfamethoxazole q12h, 7 days
400 q6h, 7 days 12 1.18
(1.05, 1.32)
1.18
(1.05, 1.33)
1.18
(1.00, 1.39)
Trimethoprim/
Sulfamethoxazole
   Sulfamethoxazole 800 Trimethoprim/
160 Sulfamethoxazole q12h, 7 days
400 q6h, 7 days 12 1.01
(0.95, 1.08)
1.05
(1.01, 1.09)
1.05
(0.97, 1.14)
Vardenafil 10 single dose 800 three times daily 18 See text below for discussion of interaction.
Zidovudine 200 three times daily, 7 days 1000 three times daily, 7 days 12 0.89
(0.73, 1.09)
1.17
(1.07, 1.29)
1.51
(0.71, 3.20)
n=4
Zidovudine/
Lamivudine
   Zidovudine 200/150 three times daily, 7 days 800 three times daily, 7 days 6, 7 1.23
(0.74, 2.03)
1.39
(1.02, 1.89)
1.08
(0.77, 1.50)
n=5, 5
Zidovudine/
Lamivudine
   Lamivudine 200/150 three times daily, 7 days 800 three times daily, 7 days 6, 7 0.73
(0.52, 1.02)
0.91
(0.66, 1.26)
0.88
(0.59, 1.33)


Table name:
CONCOMITANT DRUG CLINICAL EFFECT(S)
Amphetamines, cocaine, other sympathomimetic agents Additive hypertension, tachycardia, possibly cardiotoxicity
Atropine, scopolamine, antihistamines, other anticholinergic agents Additive or super-additive tachycardia, drowsiness
Amitriptyline, amoxapine, desipramine, other tricyclic antidepressants Additive tachycardia, hypertension, drowsiness
Barbiturates, benzodiazepines, ethanol, lithium, opioids, buspirone, antihistamines, muscle relaxants, other CNS depressants Additive drowsiness and CNS depression
Disulfiram A reversible hypomanic reaction was reported in a 28 y/o man who smoked marijuana; confirmed by dechallenge and rechallenge
Fluoxetine A 21 y/o female with depression and bulimia receiving 20 mg/day fluoxetine X 4 wks became hypomanic after smoking marijuana; symptoms resolved after 4 days
Antipyrine, barbiturates Decreased clearance of these agents, presumably via competitive inhibition of metabolism
Theophylline Increased theophylline metabolism reported with smoking of marijuana; effect similar to that following smoking tobacco


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
↓=Decreased (induces lamotrigine glucuronidation).
↑=Increased (inhibits lamotrigine glucuronidation).
?=Conflicting data.
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine Decreased lamotrigine levels approximately 50%.
 
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
 
? CBZ epoxide May increase CBZ epoxide levels
Phenobarbital/Primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT) ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine Increased lamotrigine concentrations slightly more than 2-fold.
 
? valproate Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T 4 and T 3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT 4. Continued administration results in a decrease in serum T 4 and normal FT 4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T 4 and T 3 to TBG and transthyretin. An initial increase in serum FT 4, is followed by return of FT 4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T 4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T 4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T 4 to T 3, leading to decreased T 3 levels. However, serum T 4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T 3 and T 4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T 3 concentrations by 30% with minimal change in serum T 4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T 3 and T 4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug
Effect on Concentration of Lamotrigine or 
Concomitant Drug
Clinical Comment 
↓= Decreased (induces lamotrigine gluronidation).
↑= Increased (inhibits lamotrigine glucuronidation).
?= Conflicting data.
Estrogen-containing oral 
contraceptive preparations 
containing 30 mcg ethinylestradiol 
and 150 mcg levonorgestrel
↓ lamotrigine




Decreased lamotrigine levels 
approximately 50%.



↓ levonorgestrel
Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and 
CBZ epoxide
↓ lamotrigine

Addition of carbamazepine decreases lamotrigine 
concentration approximately 40%.

? CBZ epoxide
May increase CBZ epoxide levels
Phenobarbital/Primidone
↓ lamotrigine
Decreased lamotrigine 
concentration approximately 40%.
Phenytoin (PHT)
↓ lamotrigine
Decreased lamotrigine 
concentration approximately 40%
Rifampin
↓ lamotrigine
Decreased lamotrigine AUC 
approximately 40%
Valproate
↑ lamotrigine

Increased lamotrigine concentrations slightly 
more than 2-fold.

? valproate
Decreased valproate concentrations an average of 
25% over a 3-week period then stabilized in healthy volunteers; 
no change in controlled clinical trials in epilepsy patients.



Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
edema
hereditary coumarin resistance
hyperlipemia
hypothyroidism
nephrotic syndrome


Table name:
Table 3Drugs that Can Increase the Risk of Bleeding
Drug  Class
Specific  Drugs
Anticoagulants 
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin 
Antiplatelet Agents 
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine 
Nonsteroidal Anti-Inflammatory Agents 
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac 
Serotonin Reuptake Inhibitors 
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone 


Table name:
CONCOMITANT DRUG CLINICAL EFFECT(S)
Amphetamines, cocaine, other sympathomimetic
agents
Additive hypertension, tachycardia, possibly cardiotoxicity
Atropine, scopolamine, antihistamines, other
anticholinergic agents
Additive or super-additive tachycardia, drowsiness
Amitriptyline, amoxapine, desipramine, other
tricyclic antidepressants
Additive tachycardia, hypertension, drowsiness
Barbiturates, benzodiazepines, ethanol, lithium,
opioids, buspirone, antihistamines, muscle relaxants,
other CNS depressants
Additive drowsiness and CNS depression
Disulfiram A reversible hypomanic reaction was reported in a 28 y/o
man who smoked marijuana; confirmed by dechallenge and
rechallenge
Fluoxetine A 21 y/o female with depression and bulimia receiving 20
mg/day fluoxetine X 4 wks became hypomanic after
smoking marijuana; symptoms resolved after 4 days
Antipyrine, barbiturates Decreased clearance of these agents, presumably via
competitive inhibition of metabolism
Theophylline Increased theophylline metabolism reported with smoking of
marijuana; effect similar to that following smoking tobacco
Opioids Cross-tolerance and mutual potentiation
Naltrexone Oral THC effects were enhanced by opioid receptor
blockade.
Alcohol Increase in the positive subjective mood effects of smoked
marijuana


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.3, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Grapefruit juice Avoid grapefruit juice


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir ) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
 Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration  Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
 Drugs that may alter T 4 and T 3 metabolism
 Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 4: Clinically Relevant Interactions Affecting Omeprazole When Co-Administered with Other Drugs
CYP2C19 or CYP3A4 Inducers
Clinical Impact:
Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology (12.3) ].
Intervention:
St. John’s Wort, rifampin: Avoid concomitant use with omeprazole [see Warnings and Precautions (5.9) ].
Ritonavir-containing products: see prescribing information for specific drugs.
CYP2C19 or CYP3A4 Inhibitors
Clinical Impact:
Increased exposure of omeprazole [see Clinical Pharmacology (12.3) ].
Intervention:
Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered.
 
See prescribing information for voriconazole.


Table name:
edema
hereditary coumarin resistance
hyperlipemia
hypothyroidism
nephrotic syndrome


Table name:
Table 5. Drugs That May Decrease Conversion of T4 to T3
Potential impact: Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased.
Drug or Drug Class Effect
Beta-adrenergic antagonists
(e.g., Propranolol > 160 mg/day)
In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change, TSH levels remain normal, and patients are clinically euthyroid. Actions of particular beta-adrenergic antagonists may be impaired when a hypothyroid patient is converted to the euthyroid state.
Glucocorticoids
(e.g., Dexamethasone > 4 mg/day)
Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (See above).
Other drugs:
Amiodarone
Amiodarone inhibits peripheral conversion of levothyroxine (T4) to triiodothyronine (T3) and may cause isolated biochemical changes (increase in serum free-T4, and decreased or normal free-T3) in clinically euthyroid patients.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Laboratory Tests Effect of Salicylates
Thyroid Function Decreased PBI; increased T3 uptake
Urinary Sugar False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5 g qd)
5 Hydroxyindole acetic acid False negative with fluorometric test
Acetone, Ketone Bodies False positive FeCl3 in Gerhardt reaction; red color persists with boiling
17-OH corticosteroids False reduced values with >4.8 g qd salicylate
Vanilmandelic Acid False reduced values
Uric Acid May increase or decrease depending on dose
Prothrombin Decreased levels; slightly increased prothrombin time


Table name:
AED Coadministered AED Concentration Topiramate Concentration
Phenytoin
NC or 25% increasePlasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
48% decrease


Carbamazepine (CBZ)
NC
40% decrease
CBZ epoxideIs not administered but is an active metabolite of carbamazepine.
NC
NE
Valproic acid
11% decrease
14% decrease
Phenobarbital
NC
NE
Primidone
NC
NE
Lamotrigine
NC at TPM doses up to 400 mg/day
13% decrease


Table name:
Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s) Recommendation Comments
Tizanidine Contraindicated Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)].
Theophylline Avoid Use (Plasma Exposure Likely to be Increased and Prolonged) Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions (5.6).]
Drugs Known to Prolong QT Interval Avoid Use Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.10) and Use in Specific Populations (8.5)].
Oral antidiabetic drugs Use with caution Glucose-lowering effect potentiated Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported . Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs. [see Adverse Reactions (6.1).]
Phenytoin Use with caution Altered serum levels of phenytoin (increased and decreased) To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after coadministration of ciprofloxacin with phenytoin.
Cyclosporine Use with caution (transient elevations in serum creatinine) Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs Use with caution (Increase in anticoagulant effect) The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole Use with caution Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after coadministration with ciprofloxacin [see Warnings and Precautions (5.15)].
Clozapine Use with caution Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs Use with caution Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil Use with caution 2-fold increase in exposure Monitor for sildenafil toxicity (see Pharmacokinetics -(12.3)-] .
Duloxetine Avoid Use 5-fold increase in duloxetine exposure If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx ® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products) Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2)]. Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels) Potentiation of ciprofloxacin toxicity may occur.


Table name:
Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class Specific Drugs
 Anticoagulants  argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
 Antiplatelet Agents  aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
 Nonsteroidal Anti-Inflammatory Agents  celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
 Serotonin Reuptake Inhibitors  citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors
(e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol
Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin dailyFor patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice Avoid grapefruit juice


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
 Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration  Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
 Drugs that may alter T 4 and T 3 metabolism
 Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table II. Clinically significant drug interactions with theophylline*.
DrugType of InteractionEffect**
* Refer to PRECAUTIONS, Drug Interactions for further information regarding table.
** Average effect on steady state theophylline concentration or other clinical effect forpharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.
AdenosineTheophylline blocksHigher doses of adenosine
adenosine receptors.may be required to achieve
desired effect.
AlcoholA single large dose of alcohol30% increase
(3 ml/kg of whiskey) decreases
theophylline clearance for up
to 24 hours
AllopurinolDecreases theophylline clearance25% increase at allopurinol
doses ≥600 mg/day.
Amino glutethimideIncreases theophylline clearance25% decrease
by induction of microsomal enzyme
activity.
CarbamazepineSimilar to aminoglutethimide30% decrease
CimetidineDecreases theophylline clearance70% increase
by inhibiting cytochrome P450 1A2.
CiprofloxacinSimilar to cimetidine.40% increase
ClarithromycinSimilar to erythromycin.25% increase
DiazepamBenzodiazepines increase CNSLarger diazepam doses
concentrations of adenosine, a potentmay be required to
CNS depressant, while theophyllineproduce desired level of
blocks adenosine receptors.sedation. Discontinuation
of theophylline without
reduction of diazepam
dose may result in
respiratory depression.
DisulfiramDecreases theophylline clearance50% increase
by inhibiting hydroxylation and
demethylation.
EnoxacinSimilar to cimetidine.300% increase
EphedrineSynergistic CNS effects.Increased frequency of
nausea, nervousness,
and insomnia.
ErythromycinErythromycin metabolite decreases35% increase.
theophylline clearance by inhibitingErythromycin steady-state
cytochrome P450 3A3serum concentrations
decrease by a similar amount.
EstrogenEstrogen containing oral contraceptives decrease theophylline30% increase
clearance in a dose-dependent fashion.
The effect of progesterone on theophylline
clearance is unknown.
FlurazepamSimilar to diazepam.Similar to diazepam.
FluvoxamineSimilar to cimetidine.Similar to cimetidine.
HalothaneHalothane sensitizes theIncreased risk of ventricular
myocardium to catecholamines,arrhythmias
theophylline increases release of
endogenous catecholamines.
Interferon, humanDecreases theophylline clearance.100% increase
recombinant alpha-A
Isoproterenol (IV)Increases theophylline clearance.20% decrease
KetaminePharmacologicMay lower theophylline
seizure threshold.
LithiumTheophylline increases renalLithium dose required to
lithium clearance.achieve a therapeutic
serum concentration
increased an average of
60%.
LorazepamSimilar to diazepam.Similar to diazepam.
Methotrexate (MTX)Decreases theophylline clearance.20% increase after low dose
MTX, higher dose MTX may
have a greater effect.
MexiletineSimilar to disulfiram.80% increase
MidazolamSimilar to diazepam.Similar to diazepam.
MoricizineIncreases theophylline clearance.25% decrease
PancuroniumTheophylline may antagonizeLarger dose of pancuronium may be required to
non-depolarizing neuromuscular
blocking effects; possibly due toachieve neuromuscular
phosphodiesterase inhibition.blockade.
PentoxifyllineDecreases theophylline clearance.30% increase
Phenobarbital (PB)Similar to aminoglutethimide.25% decrease after two
weeks of concurrent PB.
PhenytoinPhenytoin increases theophyllineSerum theophylline and
clearance by increasing microsomalphenytoin concentrations
enzyme activity. Theophylline decreases phenytoin absorption.decrease about 40%.
PropafenoneDecreases theophylline clearance40% increase. Beta-2
and pharmacologic interaction.blocking effect may
decrease efficacy of theophylline.
PropranololSimilar to cimetidine and100% increase. Beta-2
pharmacologic interaction.blocking effect may
decrease efficacy
of theophylline.
RifampinIncreases theophylline clearance20-40% decrease
by increasing cytochrome P450 1A2
and 3A3 activity.
SulfinpyrazoneIncreases theophylline clearance by20% decrease
increasing demethylation and hydroxyllation.
Decreases renal clearance of
theophylline.
TacrineSimilar to cimetidine, also increases90% increase
renal clearance of theophylline.
ThiabendazoleDecreases theophylline clearance.190% increase
TiclopidineDecreases theophylline clearance.60% increase
TroleandomycinSimilar to erythromycin.33-100% increase depending
on troleandomycin dose.
VerapamilSimilar to disulfiram.20% increase


Table name:
Interacting Drug
Interaction
Theophylline
Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin
Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents
Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin
Monitor phenytoin level (7)
Methotrexate
Monitor for methotrexate toxicity (7)
Cyclosporine
May increase serum creatinine. Monitor serum creatinine (7)
Multivalent cation-containing products including antacids, metal cations or didanosine
Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin (7)


Table name:
AED Co-administered AED Concentration TOPAMAX Concentration
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated
Phenytoin NC or 25% increase = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. 48% decrease
Carbamazepine (CBZ) NC 40% decrease
CBZ epoxide = Is not administered but is an active metabolite of carbamazepine. NC NE
Valproic acid 11% decrease 14% decrease
Phenobarbital NC NE
Primidone NC NE
Lamotrigine NC at TPM doses up to 400 mg/day 13% decrease


Table name:
Table 4. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class:
Drug Name
Effect on Concentration of Ritonavir or Concomitant Drug Clinical Comments
HIV-Antiviral Agents
HIV-1 Protease Inhibitor:
atazanavir
darunavir
fosamprenavir
↑ amprenavir
↑ atazanavir
↑ darunavir
See the complete prescribing information for fosamprenavir, atazanavir, darunavir, for details on co-administration with ritonavir.
HIV-1 Protease Inhibitor:
indinavir
↑ indinavir Appropriate doses for this combination, with respect to efficacy and safety, have not been established.
HIV-1 Protease Inhibitor:
saquinavir
↑ saquinavir See the complete prescribing information for saquinavir for details on co-administration of saquinavir and ritonavir.
Saquinavir/ritonavir in combination with rifampin is not recommended, due to the risk of severe hepatotoxicity (presenting as increased hepatic transaminases) if the three drugs are given together.
HIV-1 Protease Inhibitor:
tipranavir
↑ tipranavir See the complete prescribing information for tipranavir for details on co-administration of tipranavir and ritonavir.
Non-Nucleoside Reverse Transcriptase Inhibitor:
delavirdine
↑ ritonavir Appropriate doses of this combination with respect to safety and efficacy have not been established.
HIV-1 CCR5 – antagonist: maraviroc ↑ maraviroc See the complete prescribing information for maraviroc for details on co-administration of maraviroc and ritonavir-containing protease inhibitors.
Integrase Inhibitor:
raltegravir
↓ raltegravir The effects of ritonavir on raltegravir with ritonavir dosage regimens greater than 100 mg twice daily have not been evaluated, however raltegravir concentrations may be decreased with ritonavir coadministration.
Other Agents
Analgesics, Narcotic:
tramadol, propoxyphene,
methadone,

fentanyl
↑ analgesics

↓ methadone


↑ fentanyl
A dose decrease may be needed for these drugs when co-administered with ritonavir.

Dosage increase of methadone may be considered.


Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with NORVIR.
Anesthetic:
meperidine
↓ meperidine/ ↑ normeperidine (metabolite) Dosage increase and long-term use of meperidine with ritonavir are not recommended due to the increased concentrations of the metabolite normeperidine which has both analgesic activity and CNS stimulant activity (e.g., seizures).
Antialcoholics:
disulfiram/metronidazole
  Ritonavir formulations contain ethanol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).
Antiarrhythmics:
disopyramide, lidocaine, mexiletine
↑ antiarrhythmics For contraindicated antiarrhythmics [see Contraindications (4)].
Caution is warranted and therapeutic concentration monitoring is recommended for antiarrhythmics when co-administered with ritonavir, if available.
Anticancer Agents:
dasatinib, nilotinib,
venetoclax,
vincristine, vinblastine
↑ anticancer agents For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when ritonavir is administered concurrently with vincristine or vinblastine. Clinicians should be aware that if the ritonavir containing regimen is withheld for a prolonged period, consideration should be given to altering the regimen to not include a CYP3A or P-gp inhibitor in order to control HIV-1 viral load.A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as NORVIR. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions.

Coadministration of venetoclax and NORVIR may increase the risk of tumor lysis syndrome. Refer to the venetoclax prescribing information for dosing instructions.
Anticoagulant:
warfarin
↑↓ warfarin Initial frequent monitoring of the INR during ritonavir and warfarin co-administration is recommended.
Anticoagulant:
rivaroxaban
↑ rivaroxaban Avoid concomitant use of rivaroxaban and ritonavir. Co-administration of ritonavir and rivaroxaban may lead to risk of increased bleeding.
Anticonvulsants:
carbamazepine, clonazepam, ethosuximide
↑ anticonvulsants A dose decrease may be needed for these drugs when co-administered with ritonavir and therapeutic concentration monitoring is recommended for these anticonvulsants, if available.
Anticonvulsants:
divalproex, lamotrigine, phenytoin
↓ anticonvulsants A dose increase may be needed for these drugs when co-administered with ritonavir and therapeutic concentration monitoring is recommended for these anticonvulsants, if available.
Antidepressants:
nefazodone,
selective serotonin
reuptake inhibitors
(SSRIs): e.g.
fluoxetine,
paroxetine,
tricyclics: e.g.
amitriptyline,
nortriptyline
↑ antidepressants A dose decrease may be needed for these drugs when co-administered with ritonavir.
Antidepressant:
bupropion
↓ bupropion
↓ active metabolite, hydroxybupropion
Patients receiving ritonavir and bupropion concurrently should be monitored for an adequate clinical response to bupropion.
Antidepressant:
desipramine
↑ desipramine Dosage reduction and concentration monitoring of desipramine is recommended.
Antidepressant:
trazodone
↑ trazodone Adverse events of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and NORVIR. A lower dose of trazodone should be considered.
Antiemetic:
dronabinol
↑ dronabinol A dose decrease of dronabinol may be needed when co-administered with ritonavir.
Antifungal:
ketoconazole
itraconazole
voriconazole
↑ ketoconazole
↑ itraconazole
↓ voriconazole
For contraindicated antifungals, [see Contraindications (4)].
High doses of ketoconazole or itraconazole (greater than 200 mg per day) are not recommended.

Co-administration of voriconazole and ritonavir doses of 400 mg every 12 hours or greater is contraindicated [see Contraindications (4)]. Co-administration of voriconazole and ritonavir 100 mg should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole.
Anti-gout:
colchicine
↑ colchicine Concomitant administration with colchicine is contraindicated in patients with renal and/or hepatic impairment [see Contraindications (4)].
For patients with normal renal or hepatic function:

Treatment of gout flares-co-administration of colchicine in patients on ritonavir:

0.6 mg (one tablet) for one dose, followed by 0.3 mg (half tablet) one hour later. Dose to be repeated no earlier than three days.

Prophylaxis of gout flares-co-administration of colchicine in patients on ritonavir:

If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.

If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.

Treatment of familial Mediterranean fever (FMF)-co-administration of colchicine in patients on ritonavir:

Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Anti-infective:
clarithromycin
↑ clarithromycin For patients with renal impairment, adjust clarithromycin dose as follows:
For patients with CLCR 30 to 60 mL per min the dose of clarithromycin should be reduced by 50%. For patients with CLCR less than 30 mL per min the dose of clarithromycin should be decreased by 75%. No dose adjustment for patients with normal renal function is necessary.
Antimycobacterial:
bedaquiline
↑ bedaquiline Bedaquiline should only be used with ritonavir if the benefit of co-administration outweighs the risk.
Antimycobacterial:
rifabutin
↑ rifabutin and rifabutin metabolite Dosage reduction of rifabutin by at least three-quarters of the usual dose of 300 mg per day is recommended (e.g., 150 mg every other day or three times a week). Further dosage reduction may be necessary.
Antimycobacterial:
rifampin
↓ ritonavir May lead to loss of virologic response. Alternate antimycobacterial agents such as rifabutin should be considered.
Antiparasitic:
atovaquone
↓ atovaquone Clinical significance is unknown; however, increase in atovaquone dose may be needed.
Antiparasitic:
quinine
↑ quinine A dose decrease of quinine may be needed when co-administered with ritonavir.
Antipsychotics: perphenazine,
risperidone,
thioridazine
↑ antipsychotics For contraindicated antipsychotics, [see Contraindications (4)].
A dose decrease may be needed for these drugs when co-administered with ritonavir.
Antipsychotics:
quetiapine
↑ quetiapine Initiation of NORVIR in patients taking quetiapine:

Consider alternative antiretroviral therapy to avoid increases in quetiapine exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring.

Initiation of quetiapine in patients taking NORVIR:

Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.
β-Blockers:
metoprolol, timolol
↑ beta-blockers Caution is warranted and clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when co-administered with ritonavir.
Bronchodilator:
theophylline
↓ theophylline Increased dosage of theophylline may be required; therapeutic monitoring should be considered.
Calcium channel blockers:
diltiazem, nifedipine, verapamil
↑ calcium channel blockers Caution is warranted and clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when co-administered with ritonavir.
Digoxin ↑ digoxin Concomitant administration of ritonavir with digoxin may increase digoxin levels. Caution should be exercised when co-administering ritonavir with digoxin, with appropriate monitoring of serum digoxin levels.
Endothelin receptor antagonists: bosentan ↑ bosentan Co-administration of bosentan in patients on ritonavir:

In patients who have been receiving ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

Co-administration of ritonavir in patients on bosentan:

Discontinue use of bosentan at least 36 hours prior to initiation of ritonavir.

After at least 10 days following the initiation of ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Hepatitis C direct acting antiviral:
simeprevir
↑simeprevir It is not recommended to co-administer ritonavir with simeprevir.
HMG-CoA Reductase Inhibitor:
atorvastatin
rosuvastatin
↑ atorvastatin
↑ rosuvastatin
For contraindicated HMG-CoA Reductase inhibitors, [see Contraindications (4)].
Titrate atorvastatin and rosuvastatin dose carefully and use the lowest necessary dose.
If NORVIR is used with another protease inhibitor, see the complete prescribing information for the concomitant protease inhibitor for details on co-administration with atorvastatin and rosuvastatin.
Immunosuppressants:
cyclosporine, tacrolimus, sirolimus (rapamycin)
↑ immunosuppressants Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with ritonavir.
Systemic/Inhaled/ Nasal/Ophthalmic Corticosteroids:
e.g.,
betamethasone
budesonide
ciclesonide
dexamethasone
fluticasone
methylprednisolone
mometasone
prednisone
triamcinolone
↑ glucocorticoids Coadministration with corticosteroids whose exposures are significantly increased by strong CYP3A inhibitors can increase the risk for Cushing’s syndrome and adrenal suppression.

Alternative corticosteroids including beclomethasone and prednisolone (whose PK and/or PD are less affected by strong CYP3A inhibitors relative to other studied steroids) should be considered, particularly for long-term use.
Long-acting beta-adrenoceptor agonist: salmeterol ↑ salmeterol Concurrent administration of salmeterol and ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Oral Contraceptives or Patch Contraceptives:
ethinyl estradiol
↓ ethinyl estradiol Alternate methods of contraception should be considered.
PDE5 Inhibitors:
avanafil
sildenafil,
tadalafil,
vardenafil
↑ avanafil
↑ sildenafil
↑ tadalafil
↑ vardenafil
For contraindicated PDE5 inhibitors, [see Contraindications (4)].
Do not use ritonavir with avanafil because a safe and effective avanafil dosage regimen has not been established.

Particular caution should be used when prescribing sildenafil, tadalafil or vardenafil in patients receiving ritonavir. Coadministration of ritonavir with these drugs may result in an increase in PDE5 inhibitor associated adverse events, including hypotension, syncope, visual changes, and prolonged erection.

Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH):

Sildenafil (Revatio®) is contraindicated [see Contraindications (4)].

The following dose adjustments are recommended for use of tadalafil (Adcirca®) with ritonavir:

Co-administration of ADCIRCA in patients on ritonavir:

In patients receiving ritonavir for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Co-administration of ritonavir in patients on ADCIRCA:

Avoid use of ADCIRCA during the initiation of ritonavir. Stop ADCIRCA at least 24 hours prior to starting ritonavir. After at least one week following the initiation of ritonavir, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Use of PDE5 inhibitors for the treatment of erectile dysfunction:

It is recommended not to exceed the following doses:
Sildenafil: 25 mg every 48 hours Tadalafil: 10 mg every 72 hours Vardenafil: 2.5 mg every 72 hours Use with increased monitoring for adverse events.
Sedative/hypnotics:
buspirone, clorazepate, diazepam, estazolam, flurazepam, zolpidem
↑ sedative/hypnotics A dose decrease may be needed for these drugs when co-administered with ritonavir.
Sedative/hypnotics: Parenteral midazolam
↑ midazolam For contraindicated sedative/hypnotics, [see Contraindications (4) ].
Co-administration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered.
Stimulant:
methamphetamine
↑ methamphetamine Use with caution. A dose decrease of methamphetamine may be needed when co-administered with ritonavir.


Table name: Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.During concomitant use of diclofenac sodium delayed-release tablets and ACE-inhibitors, ARBs, or beta- blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of diclofenac sodium delayed-release tablets and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS: Renal Toxicity and Hyperkalemia ). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Table 2. Clinically Significant Drug Interactions with Diclofenac
Drugs That Interfere with Hemostasis
Clinical Impact:
Intervention: Monitor patients with concomitant use of diclofenac sodium delayed-release tablets with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS: Hematologic Toxicity ).
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation ).
Intervention: Concomitant use of diclofenac sodium delayed-release tablets and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS: Hematologic Toxicity ). Diclofenac sodium delayed-release tablets are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:
Intervention:
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of diclofenac sodium delayed-release tablets with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS: Renal Toxicity and Hyperkalemia ).
Digoxin
Clinical Impact: The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of diclofenac sodium delayed-release tablets and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of diclofenac sodium delayed-release tablets and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of diclofenac sodium delayed-release tablets and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of diclofenac sodium delayed-release tablets and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of diclofenac sodium delayed-release tablets and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation ).
Intervention: The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of diclofenac sodium delayed-release tablets and pemetrexed may increase the risk of pemetrexed‑ associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of diclofenac sodium delayed-release tablets and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
CYP2C9 Inhibitors or Inducers:
Clinical Impact: Diclofenac is metabolized by cytochrome P450 enzymes, predominantly by CYP2C9. Co-administration of diclofenac with CYP2C9 inhibitors (e.g. voriconazole) may enhance the exposure and toxicity of diclofenac whereas co‑administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of diclofenac.
Intervention: A dosage adjustment may be warranted when diclofenac is administered with CYP2C9 inhibitors or inducers (see CLINICAL PHARMACOLOGY: Pharmacokinetics ).


Table name:
Table 7: Summary of AED Interactions with Oxcarbazepine
AED Coadministered Dose of AED (mg/day) Oxcarbazepine Dose (mg/day) Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval) Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine 400 to 2000 900 ncnc denotes a mean change of less than 10% 40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital 100 to 150 600 to 1800 14% increase [CI: 2% increase, 24% increase] 25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin 250 to 500 600 to 1800 >1200 to 2400 nc , Pediatrics up to 40% increaseMean increase in adults at high oxcarbazepine doses [CI: 12% increase, 60% increase] 30% decrease [CI: 3% decrease, 48% decrease]
Valproic acid 400 to 2800 600 to 1800 nc 18% decrease [CI: 13% decrease, 40% decrease]


Table name:
Interacting  Agents 
Prescribing  Recommendations 
Itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine, danazol 
Contraindicated with simvastatin
Amiodarone, verapamil, diltiazem
Do not exceed 10 mg simvastatin daily 
Amlodipine, ranolazine
Do not exceed 20 mg simvastatin daily 
Grapefruit juice 
Avoid large quantities of grapefruit juice (>1 quart daily) 


Table name:
AED Coadministered AED Concentration Topiramate Concentration
Phenytoin
NC or 25% increase Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
48% decrease


Carbamazepine (CBZ)
NC
40% decrease
CBZ epoxide Is not administered but is an active metabolite of carbamazepine.
NC
NE
Valproic acid
11% decrease
14% decrease
Phenobarbital
NC
NE
Primidone
NC
NE
Lamotrigine
NC at TPM doses up to 400 mg/day
13% decrease


Table name:
Table 13 Established and Other Potentially Significant Drug Interactions
Concomitant Drug
Effect on Concentration of Lamotrigine or Concomitant Drug
Clinical Comment
↓ = Decreased (induces lamotrigine glucuronidation)
↑ = Increased (inhibits lamotrigine glucuronidation)
? = Conflicting data
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel
↓ lamotrigine
Decreased lamotrigine concentrations approximately 50%
↓ levonorgestrel
Decrease in levonorgestrel component by 19%
Carbamazepine and Carbamazepine
epoxide
↓ lamotrigine
Addition of carbamazepine decreases lamotrigine concentration approximately 40%
? Carbamazepine
epoxide
May increase carbamazepine epoxide levels.
Lopinavir/ritonavir
↓ lamotrigine
Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir
↓ lamotrigine
Decreased lamotrigine AUC approximately 32%.
Phenobarbital/Primidone
↓ lamotrigine
Decreased lamotrigine concentration approximately 40%
Phenytoin
↓ lamotrigine
Decreased lamotrigine concentration approximately 40%
Rifampin
↓ lamotrigine
Decreased lamotrigine AUC approximately 40%
Valproate
↑ lamotrigine
Increased lamotrigine concentrations slightly more than 2-fold
? valproate
There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.


Table name:
AED Co-administered AED Concentration Topiramate Concentration
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated
Phenytoin NC or 25% increase= Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. 48% decrease
Carbamazepine (CBZ) NC 40% decrease
CBZ epoxide= Is not administered but is an active metabolite of carbamazepine. NC NE
Valproic acid 11% decrease 14% decrease
Phenobarbital NC NE
Primidone NC NE
Lamotrigine NC at TPM doses up to 400 mg/day 13% decrease


Table name:
Table 8. Effect of Voriconazole on Pharmacokinetics of Other Drugs
[see Clinical Pharmacology (12.3) ]
Drug/Drug Class
(Mechanism of
Interaction by
Voriconazole)
Drug Plasma Exposure
(Cmax and AUCτ)
Recommendations for Drug Dosage
Adjustment/Comments
Sirolimus*
(CYP3A4 Inhibition)
Significantly Increased Contraindicated
Rifabutin*
(CYP3A4 Inhibition)
Significantly Increased Contraindicated
Efavirenz**
(CYP3A4 Inhibition)
Significantly Increased When voriconazole is coadministered with
 efavirenz, voriconazole oral maintenance
 dose should be increased to 400 mg every 12h and
 efavirenz should be decreased to 300 mg every 24h
High-dose Ritonavir
(400 mg every 12h)**
(CYP3A4 Inhibition)
 
Low-dose Ritonavir
(100 mg every 12h)**
No Significant Effect of Voriconazole on
 Ritonavir Cmax or AUCτ 
  
 
Slight Decrease in Ritonavir Cmax and AUCτ
Contraindicated because of significant reduction of voriconazole Cmax and AUCτ 
  
 
Coadministration of voriconazole and low-dose ritonavir (100 mg every 12h) should be avoided (due to the reduction in voriconazole Cmax and AUCτ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine
(CYP3A4 Inhibition)
Not Studied  In Vivo  or  In Vitro , but Drug
 Plasma Exposure Likely to be Increased
Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids
(CYP450 Inhibition)
Not Studied  In Vivo  or  In Vitro , but Drug
 Plasma Exposure Likely to be Increased
Contraindicated
Cyclosporine*
(CYP3A4 Inhibition)
AUCτ Significantly Increased;
No Significant Effect on Cmax
When initiating therapy with Voriconazole for Injection in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When Voriconazole for Injection is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
Methadone***
(CYP3A4 Inhibition)
Increased Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl
(CYP3A4 Inhibition)
Increased Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with Voriconazole for Injection. Extended and frequent monitoring for opiate-associated adverse events may be necessary [ see Drug Interactions (7) ]
Alfentanil
(CYP3A4 Inhibition)
Significantly Increased Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with Voriconazole for Injection. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [ see Drug Interactions (7) ].
Oxycodone
(CYP3A4 Inhibition)
Significantly Increased Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with Voriconazole for Injection. Extended and frequent monitoring for opiate-associated adverse events may be necessary [ see Drug Interactions (7) ].
NSAIDs**** including
ibuprofen and diclofenac
(CYP2C9 Inhibition)
Increased Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed [ see Drug Interactions (7) ].
Tacrolimus*
(CYP3A4 Inhibition)
Significantly Increased When initiating therapy with Voriconazole for Injection in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When Voriconazole for Injection is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin*
(CYP2C9 Inhibition)
Significantly Increased Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing
ethinyl estradiol and norethindrone
(CYP3A4 Inhibition)**
Increased Monitoring for adverse events related to oral contraceptives is recommended during coadministration.
Warfarin*
(CYP2C9 Inhibition)
Prothrombin Time Significantly Increased Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed.
Omeprazole*
(CYP2C19/3A4 Inhibition)
Significantly Increased When initiating therapy with Voriconazole for Injection in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors
(CYP3A4 Inhibition)
In Vivo Studies Showed No Significant Effects on Indinavir Exposure
 
In Vitro
Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)
No dosage adjustment for indinavir when coadministered with Voriconazole for Injection
  
Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors
Other NNRTIs*****
(CYP3A4 Inhibition)
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to NNRTI
Benzodiazepines
(CYP3A4 Inhibition)
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.
HMG-CoA Reductase Inhibitors
(Statins)
(CYP3A4 Inhibition)
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel
Blockers
(CYP3A4 Inhibition)
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics
(CYP2C9 Inhibition)
Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids
(CYP3A4 Inhibition)
Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed.
*      Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg twice daily voriconazole to healthy subjects **    Results based on in vivo clinical study following repeat oral dosing with 400 mg every 12h for 1 day, then 200 mg every 12h for at least 2 days voriconazole to healthy subjects *** Results based on in vivo clinical study following repeat oral dosing with 400 mg every 12h for 1 day, then 200 mg every 12h for 4 days voriconazole to subjects receiving a methadone maintenance dose (30 to 100 mg daily) **** Non-Steroidal Anti-Inflammatory Drug ***** Non-Nucleoside Reverse Transcriptase Inhibitors


Table name:
Drugs that Affect Renal Function A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDS], COX-2 inhibitors may impair the excretion of digoxin.
Antiarrhythmics Dofetilide Concomitant administration with digoxin was associated with a higher rate of torsades de pointes.
Sotalol Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
Dronedarone Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone Analog Teriparatide Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement Thyroid Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics Epinephrine
Norepinephrine
Dopamine
Can increase the risk of cardiac arrhythmias
Neuromuscular Blocking Agents Succinylcholine May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.
Supplements Calcium If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.


Table name:
Table 4 Other Potentially Significant Drug Interactions
Concomitant Drug Class or Food Noted or anticipated Outcome Clinical Comment
HMG-Co A Reductase Inhibitors:
atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin
Pharmacokinetic and/or pharmacodynamic interaction: the addition of one drug to a stable long-term regimen of the other has resulted in myopathy and rhabdomyolysis (including a fatality) Weigh the potential benefits and risks and carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during initial therapy; monitoring CPK (creatine phosphokinase) will not necessarily prevent the occurrence of severe myopathy.
Other Lipid Lowering Drugs:
fibrates, gemfibrozil
Digitalis Glycosides:
digoxin
P-gp substrate; rhabdomyolysis has been reported


Table name:
Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
CONCOMITANT  DRUG CLINICAL EFFECT(S)        
Amphetamines, cocaine, other sympathomimetic agents Additive hypertension, tachycardia, possibly cardiotoxicity
Atropine, scopolamine, antihistamines, other anticholinergic agents Additive or super-additive tachycardia, drowsiness
Amitriptyline, amoxapine, desipramine, other tricyclic antidepressants Additive tachycardia, hypertension, drowsiness
Barbiturates, benzodiazepines, ethanol, lithium, opioids, buspirone, antihistamines, muscle relaxants, other CNS depressants Additive drowsiness and CNS depression
Disulfiram A reversible hypomanic reaction was reported in a 28 y/o man who smoked marijuana; confirmed by dechallenge and rechallenge
Fluoxetine A 21 y/o female with depression and bulimia receiving 20 mg/day fluoxetine X 4 wks became hypomanic after smoking marijuana; symptoms resolved after 4 days
Antipyrine, barbiturates Decreased clearance of these agents,presumably via competitive inhibition of metabolism
Theophylline Increased theophylline metabolism reported with smoking of marijuana; effect similar to that following smoking tobacco


Table name:
Table 3Drugs that Can Increase the Risk of Bleeding
Drug  Class
Specific  Drugs
Anticoagulants 
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin 
Antiplatelet Agents 
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine 
Nonsteroidal Anti-Inflammatory Agents 
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac 
Serotonin Reuptake Inhibitors 
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone 


Table name:
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
Lopinavir plus ritonavir Use lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Table 2: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 5 mg in BPH patients on stable alpha-blocker therapy (Study 1)
Alpha-Blocker Simultaneous dosing of Vardenafil 5 mg
and Alpha-Blocker,
Placebo-Subtracted
Dosing of Vardenafil 5 mg
and Alpha-Blocker
Separated by 6 Hours,
Placebo-Subtracted
Terazosin
5 or 10 mg daily
Standing SBP -3 (-6.7, 0.1) -4 (-7.4, -0.5)
Supine SBP -4 (-6.7, -0.5) -4 (-7.1, -0.7)
Tamsulosin
0.4 mg daily
Standing SBP
Supine SBP
-6 (-9.9, -2.1)
-4 (-7.0, -0.8)
-4 (-8.3, -0.5)
-5 (-7.9, -1.7)


Table name:
NA = Not available/reported
Digoxin concentrations increased greater than 50%
   Digoxin Serum   
Concentration Increase
   Digoxin AUC Increase Recommendations
Amiodarone 70% NA Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring.
Captopril 58% 39%
Clarithromycin NA 70%
Dronedarone NA 150%
Gentamicin 129-212% NA
Erythromycin 100% NA
Itraconazole 80% NA
Lapatinib NA 180%
Nitrendipine 57% 15%
Propafenone NA 60-270%
Quinidine 100% NA
Ranolazine 50% NA
Ritonavir NA 86%
Telaprevir 50% 85%
Tetracycline 100% NA
Verapamil 50-75% NA
Digoxin concentrations increased less than 50%
Atorvastatin 22% 15% Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring.
Carvedilol 16% 14%
Conivaptan 33% 43%
Diltiazem 20% NA
Indomethacin 40% NA
Nefazodone 27% 15%
Nifedipine 45% NA
Propantheline 24% 24%
Quinine NA 33%
Rabeprazole 29% 19%
Saquinavir 27% 49%
Spironolactone      25% NA
Telmisartan 20-49% NA
Ticagrelor 31% 28%
Tolvaptan 30% 20%
Trimethoprim 22-28% NA
Digoxin concentrations increased, but magnitude is unclear
Alprazolam, azithromycin, cyclosporine, diclofenac, diphenoxylate, epoprostenol, esomeprazole, ibuprofen, ketoconazole, lansoprazole, metformin, omeprazole Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin concentrations decreased
Acarbose, activated charcoal, albuterol, antacids, certain cancer chemotherapy or radiation therapy, cholestyramine, colestipol, extenatide, kaolin-pectin, meals high in bran, metoclopramide, miglitol, neomycin, penicillamine, phenytoin, rifampin, St. John’s Wort, sucralfate and sulfasalazine Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20-40% as necessary.


Table name:
Drugs That Interfere with Hemostasis
Clinical Impact: Indomethacin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of indomethacin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of indomethacin with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ see Warnings and Precautions ( 5.11 )].
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ see Warnings and Precautions ( 5.2 ) ].
Intervention: Concomitant use of indomethacin capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions ( 5.11 )].Indomethacin is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: During concomitant use of indomethacin capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.During concomitant use of indomethacin capsules and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ see Warnings and Precautions ( 5.6 )].When these drugs are administered concomitantly, patients should be adequately hydrated.  Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.It has been reported that the addition of triamterene to a maintenance schedule of Indomethacin resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin and triamterene should not be administered together.Both indomethacin and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently [ see Warnings and Precautions ( 5.6 )].  
Intervention: Indomethacin and triamterene should not be administered together. During concomitant use of indomethacin capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects. Be aware that indomethacin and potassium-sparing diuretics may both be associated with increased serum potassium levels. [ see Warnings and Precautions ( 5.6 )].  
Digoxin  
Clinical Impact: The concomitant use of indomethacin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.  
Intervention: During concomitant use of indomethacin capsules and digoxin, monitor serum digoxin levels.  
Lithium  
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.  
Intervention: During concomitant use of indomethacin capsules and lithium, monitor patients for signs of lithium toxicity.  
Methotrexate  
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).  
Intervention: During concomitant use of indomethacin capsules and methotrexate, monitor patients for methotrexate toxicity.  
Cyclosporine  
Clinical Impact: Concomitant use of indomethacin capsules and cyclosporine may increase cyclosporine's nephrotoxicity.  
Intervention: During concomitant use of indomethacin capsules and cyclosporine, monitor patients for signs of worsening renal function.  
NSAIDs and Salicylates  
Clinical Impact: Concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ see Warnings and Precautions ( 5.2 )]. Combined use with diflunisal may be particularly hazardous because diflunisal causes significantly higher plasma levels of indomethacin [see Clinical Pharmacology ( 12.3 )].In some patients, combined use of indomethacin and diflunisal has been associated with fatal gastrointestinal hemorrhage.  
Intervention: The concomitant use of indomethacin with other NSAIDs or salicylates, especially diflunisal, is not recommended.  
Pemetrexed  
Clinical Impact: Concomitant use of indomethacin capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).  
Intervention: During concomitant use of indomethacin capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.  
Probenecid  
Clinical Impact: When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased.  
Intervention: During the concomitant use of indomethacin and probenecid, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect.  When increases in the dose of indomethacin are made, they should be made carefully and in small increments.  


Table name:
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin dailyFor patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice Avoid grapefruit juice


Table name:
Drugs That Are Affected By Clarithromycin
Drug(s) with Pharmacokinetics Affected by Clarithromycin
Recommendation
Comments
Antiarrhythmics:
 
Disopyramide
Quinidine
Dofetilide
Amiodarone
Sotalol
Procainamide
 
 
 
 
Digoxin
 
 
Not Recommended
 
 
 
 
 
 
 
 
Use With Caution
 
 
Disopyramide, Quinidine: There have been postmarketing reports of torsades de pointes occurring with concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QTc prolongation during coadministration of clarithromycin with these drugs [see Warnings and Precautions (5.3)].
 
Serum concentrations of these medications should also be monitored. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with disopyramide and quinidine.
 
There have been postmarketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide. Therefore, blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide.
 
Digoxin: Digoxin is a substrate for P-glycoprotein (Pgp) and clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are co-administered, inhibition of Pgp by clarithromycin may lead to increased exposure of digoxin. Elevated digoxin serum concentrations in patients receiving clarithromycin and digoxin concomitantly have been reported in postmarketing surveillance. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Monitoring of serum digoxin concentrations should be considered, especially for patients with digoxin concentrations in the upper therapeutic range.
Oral Anticoagulants:
 
Warfarin
 
 
Use With Caution
 
 
Oral anticoagulants: Spontaneous reports in the postmarketing period suggest that concomitant administration of clarithromycin and oral anticoagulants may potentiate the effects of the oral anticoagulants. Prothrombin times should be carefully monitored while patients are receiving clarithromycin and oral anticoagulants simultaneously [see Warnings and Precautions (5.4)].
Antiepileptics:
 
Carbamazepine
 
 
Use With Caution
 
 
Carbamazepine: Concomitant administration of single doses of clarithromycin and carbamazepine has been shown to result in increased plasma concentrations of carbamazepine. Blood level monitoring of carbamazepine may be considered. Increased serum concentrations of carbamazepine were observed in clinical trials with clarithromycin. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with carbamazepine.
Antifungals:
 
Itraconazole
 
 
 

Fluconazole
 
 
Use With Caution
 
 
 

No Dose Adjustment
 
 
Itraconazole: Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when administered concomitantly (see also Itraconazole under “Drugs That Affect Clarithromycin” in the table below). Clarithromycin may increase the plasma concentrations of itraconazole. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions.
 
Fluconazole:  [see Pharmacokinetics (12.3)]
 
Anti-Gout Agents:
 
Colchicine (in patients with renal or hepatic impairment)
 
Colchicine (in patients with normal renal and hepatic function)
 
 
Contraindicated
 
 
Use With Caution
 
 
Colchicine: Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. The dose of colchicine should be reduced when co-administered with clarithromycin in patients with normal renal and hepatic function [see Contraindications (4.4) and Warnings and Precautions (5.4)].
Antipsychotics:
 
Pimozide
 
Quetiapine
 
 
Contraindicated
 
 
Pimozide:  [See Contraindications (4.2)]

Quetiapine: Quetiapine is a substrate for CYP3A4, which is inhibited by clarithromycin. Co-administration with clarithromycin could result in increased quetiapine exposure and possible quetiapine related toxicities. There have been postmarketing reports of somnolence, orthostatic hypotension, altered state of consciousness, neuroleptic malignant syndrome, and QT prolongation during concomitant administration. Refer to quetiapine prescribing information for recommendations on dose reduction if co-administered with CYP3A4 inhibitors such as clarithromycin.
Antispasmodics:
 
Tolterodine (patients deficient in CYP2D6 activity)
 
 
Use With Caution
 
 
Tolterodine: The primary route of metabolism for tolterodine is via. CYP2D6. However, in a subset of the population devoid of CYP2D6, the identified pathway of metabolism is via. CYP3A. In this population subset, inhibition of CYP3A results in significantly higher serum concentrations of tolterodine. Tolterodine 1 mg twice daily is recommended in patients deficient in CYP2D6 activity (poor metabolizers) when co-administered with clarithromycin.
Antivirals:
 
Atazanavir
 

Saquinavir (in patients with decreased renal function)
 
Ritonavir
Etravirine
 
Maraviroc
 

Boceprevir (in patients with normal renal function)
 
Didanosine
 
Zidovudine


 
 
Use With Caution
 
 
 
 
 
 
 
 
 
 

No Dose Adjustment
 
 
Atazanavir: Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction (see Atazanavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)].
 
Saquinavir: Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A and there is evidence of a bi-directional drug interaction (see Saquinavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)].
 
Ritonavir, Etravirine: (see Ritonavir and Etravirine under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)].
 

Maraviroc: Clarithromycin may result in increases in maraviroc exposures by inhibition of CYP3A metabolism. See Selzentry® prescribing information for dose recommendation when given with strong CYP3A inhibitors such as clarithromycin.
 
Boceprevir: Both clarithromycin and boceprevir are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when co-administered. No dose adjustments are necessary for patients with normal renal function (see Victrelis® prescribing information).
 


Zidovudine: Simultaneous oral administration of clarithromycin immediate-release tablets and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine concentrations. Administration of clarithromycin and zidovudine should be separated by at least two hours [see Pharmacokinetics (12.3)].
Calcium Channel Blockers:
 
Verapamil
 

Amlodipine
Diltiazem
 
Nifedipine
 
 
Use With Caution
 
 
Verapamil: Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent verapamil, [see Warnings and Precautions (5.4)].
 
Amlodipine, Diltiazem: [See Warnings and Precautions (5.4)]

 
Nifedipine: Nifedipine is a substrate for CYP3A. Clarithromycin and other macrolides are known to inhibit CYP3A. There is potential of CYP3A-mediated interaction between nifedipine and clarithromycin. Hypotension and peripheral edema were observed when clarithromycin was taken concomitantly with nifedipine [see Warnings and Precautions (5.4)].
Ergot Alkaloids:
 
Ergotamine
Dihydroergotamine
 
 
Contraindicated
 
 
Ergotamine, Dihydroergotamine: Postmarketing reports indicate that coadministration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system [see Contraindications (4.6)].
Gastroprokinetic  Agents:
 
Cisapride
 
 
Contraindicated
 
 
Cisapride: [See Contraindications (4.2)]
HMG-CoA Reductase Inhibitors:
 
Lovastatin
Simvastatin
 
Atorvastatin
Pravastatin
 
Fluvastatin

 
 
Contraindicated
 
 
Use With Caution
 
No Dose Adjustment
 
 
Lovastatin, Simvastatin, Atorvastatin, Pravastatin, Fluvastatin:  [See Contraindications (4.5) and Warnings and Precautions (5.4)]
Hypoglycemic Agents:
 
Nateglinide
Pioglitazone
Repaglinide
Rosiglitazone
 
Insulin

 
 
Use With Caution
 
 
Nateglinide, Pioglitazone, Repaglinide, Rosiglitazone: [See Warnings and Precautions (5.4) and Adverse Reactions (6.2)]
 



Insulin: [See Warnings and Precautions (5.4) and Adverse Reactions (6.2)]
Immunosuppressants:
 
Cyclosporine
 
Tacrolimus
 
 
Use With Caution
 
 
Cyclosporine: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with cyclosporine.
 
Tacrolimus: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with tacrolimus.
Phosphodiesterase inhibitors:
 
Sildenafil
Tadalafil
Vardenafil
 
 
 
Use With Caution
 
 
 
Sildenafil, Tadalafil, Vardenafil: Each of these phosphodiesterase inhibitors is primarily metabolized by CYP3A, and CYP3A will be inhibited by concomitant administration of clarithromycin. Co-administration of clarithromycin with sildenafil, tadalafil, or vardenafil will result in increased exposure of these phosphodiesterase inhibitors. Co-administration of these phosphodiesterase inhibitors with clarithromycin is not recommended. Increased systemic exposure of these drugs may occur with clarithromycin; reduction of dosage for phosphodiesterase inhibitors should be considered (see their respective prescribing information).
Proton Pump Inhibitors:
 
Omeprazole
 
 
No Dose Adjustment
 
 
Omeprazole: The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when coadministered with clarithromycin as a result of increased omeprazole exposures [see Pharmacokinetics (12.3)] (see also Omeprazole under “Drugs That Affect Clarithromycin” in the table below).
Xanthine Derivatives:
 
Theophylline
 
 
Use With Caution
 
 
Theophylline: Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serum theophylline concentrations [see Pharmacokinetics (12.3)]. Monitoring of serum theophylline concentrations should be considered for patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range.
Triazolobenzodiazepines and Other Related Benzodiazepines:
 
Midazolam
 
 
Alprazolam
Triazolam
 
 
 
 
 
Temazepam
Nitrazepam
Lorazepam
 
 
 
Use With Caution
 
 
 
 
 
 
 
 
 
No Dose Adjustment
 
 
 
Midazolam: When oral midazolam is co-administered with clarithromycin, dose adjustments may be necessary and possible prolongation and intensity of effect should be anticipated [see Warnings and Precautions (5.4) and Pharmacokinetics (12.3)].
 
Triazolam, Alprazolam: Caution and appropriate dose adjustments should be considered when triazolam or alprazolam is co-administered with clarithromycin. There have been postmarketing reports of drug interactions and central nervous system (CNS) effects (e.g., somnolence and confusion) with the concomitant use of clarithromycin and triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested.
 
In postmarketing experience, erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines.
 
Temazepam, Nitrazepam, Lorazepam: For benzodiazepines which are not metabolized by CYP3A (e.g., temazepam, nitrazepam, lorazepam), a clinically important interaction with clarithromycin is unlikely.
Cytochrome P450 Inducers:
 
Rifabutin
 
 
Use With Caution
 
 
Rifabutin: Concomitant administration of rifabutin and clarithromycin resulted in an increase in rifabutin, and decrease in clarithromycin serum levels together with an increased risk of uveitis (see Rifabutin under “Drugs That Affect Clarithromycin” in the table below).
Other Drugs
Metabolized by CYP3A:
 
Alfentanil
Bromocriptine
Cilostazol
Methylprednisole Vinblastine
Phenobarbital
St. John’s Wort
 
 
 
Use With Caution
 
 
 
There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with alfentanil, methylprednisolone, cilostazol, bromocriptine, vinblastine, phenobarbital, and St. John’s Wort.
Other Drugs Metabolized by CYP450 Isoforms Other than CYP3A:
 
Hexobarbital
Phenytoin
Valproate
 
 
 
 
Use With Caution
 
 
 
 
There have been postmarketing reports of interactions of clarithromycin with drugs not thought to be metabolized by CYP3A, including hexobarbital, phenytoin, and valproate.


                                                                                                                                       Drugs that Affect Clarithromycin
Drug(s) that Affect the Pharmacokinetics of Clarithromycin

Recommendation

                                                                                     Comments
Antifungals:
 
Itraconazole
 
 
Use With Caution
 
 
Itraconazole: Itraconazole may increase the plasma concentrations of clarithromycin. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions (see also Itraconazole under “Drugs That Are Affected By Clarithromycin” in the table above).
Antivirals:
 
Atazanavir
 
 
 
 
 
 
Ritonavir (in patients with decreased renal function)
 
 
Saquinavir (in patients with decreased renal function)
 
Etravirine
 
 
 
 
Saquinavir (in patients with normal renal function) Ritonavir (in patients with normal renal function)
 
 
Use With Caution
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
No Dose Adjustment
 
 
Atazanavir: When clarithromycin is co-administered with atazanavir, the dose of clarithromycin should be decreased by 50% [see Clinical Pharmacology (12.3)].
 
Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with atazanavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium complex. Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.
 
Ritonavir: Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with ritonavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium [see Pharmacokinetics (12.3)].
 
Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.
 
Saquinavir: When saquinavir is co-administered with ritonavir, consideration should be given to the potential effects of ritonavir on clarithromycin (refer to ritonavir above) [see Pharmacokinetics (12.3)].
 
Etravirine: Clarithromycin exposure was decreased by etravirine; however, concentrations of the active metabolite, 14-OH-clarithromycin, were increased. Because 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered; therefore alternatives to clarithromycin should be considered for the treatment of MAC.
Proton Pump Inhibitors:
 
Omeprazole
 
 
Use With Caution
 
 
Omeprazole: Clarithromycin concentrations in the gastric tissue and mucus were also increased by concomitant administration of omeprazole [see Pharmacokinetics (12.3)].
Miscellaneous Cytochrome P450 Inducers:
 
Efavirenz
Nevirapine
Rifampicin
Rifabutin
Rifapentine
 
 
 
Use With Caution
 
 
 
Inducers of CYP3A enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine will increase the metabolism of clarithromycin, thus decreasing plasma concentrations of clarithromycin, while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. Alternative antibacterial treatment should be considered when treating patients receiving inducers of CYP3A. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with rifabutin (see Rifabutin under “Drugs That Are Affected By Clarithromycin” in the table above).


Table name: Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology (12.3)]. Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see Clinical Pharmacology (12.3)]. There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole.
Table 3: Clinically Relevant Interactions Affecting Drugs Co-Administered with Omeprazole and Interaction with Diagnostics
Antiretrovirals
Clinical Impact:
The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known.
Intervention:
Rilpivirine-containing products: Concomitant use with omeprazole is contraindicated [see Contraindications (4)].
 
Atazanavir: Avoid concomitant use with omeprazole. See prescribing information for atazanavir for dosing information.
 
Nelfinavir: Avoid concomitant use with omeprazole. See prescribing information for nelfinavir.
 
Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities.
 
Other antiretrovirals: See prescribing information for specific antiretroviral drugs.
Warfarin
Clinical Impact:
Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
Intervention:
Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range.
Methotrexate
Clinical Impact:
Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions (5.11)].
Intervention:
A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate.
CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam)
Clopidogrel
Clinical Impact:
Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology (12.3)].
There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel.
Intervention:
Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy [see Warnings and Precautions (5.6)].
Citalopram
Clinical Impact:
Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology (12.3)].
Intervention:
Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.
Cilostazol
Clinical Impact:
Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology (12.3)].
Intervention:
Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.
Phenytoin
Clinical Impact:
Potential for increased exposure of phenytoin.
Intervention:
Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin.
Diazepam
Clinical Impact:
Increased exposure of diazepam [see Clinical Pharmacology (12.3)].
Intervention:
Monitor patients for increased sedation and reduce the dose of diazepam as needed.
Digoxin
Clinical Impact:
Potential for increased exposure of digoxin [see Clinical Pharmacology (12.3)].
Intervention:
Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)
Clinical Impact:
Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
Intervention:
Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF [see Clinical Pharmacology (12.3)].
 
See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact:
Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions.
Intervention:
See Contraindications, Warnings and Precautions  in prescribing information for clarithromycin.
 
See Drug Interactions in prescribing information for amoxicillin.
Tacrolimus
Clinical Impact:
Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.
Intervention:
Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact:
Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions (5.10), Clinical Pharmacology (12.2)].
Intervention:
Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
Interaction with Secretin Stimulation Test
Clinical Impact:
Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention:
Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology (12.2)].
False Positive Urine Tests for THC
Clinical Impact:
There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.
Intervention:
An alternative confirmatory method should be considered to verify positive results.
Other
Clinical Impact:
There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram).
Intervention:
Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole.


Table name:
Table 3Drugs that Can Increase the Risk of Bleeding
Drug  Class
Specific  Drugs
Anticoagulants 
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin 
Antiplatelet Agents 
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine 
Nonsteroidal Anti-Inflammatory Agents 
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac 
Serotonin Reuptake Inhibitors 
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone 


Table name:
Table 5. Clinically-Significant Drug Interactions with Sertraline Hydrochloride
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:
The concomitant use of SSRIs including sertraline hydrochloride and MAOIs increases the risk of serotonin syndrome.
Intervention:
Sertraline hydrochloride is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [See Dosage and Administration (2.5), Contraindications (4), Warnings and Precautions (5.2)].
Examples:
selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue
Pimozide
Clinical Impact:
Increased plasma concentrations of pimozide, a drug with a narrow therapeutic index, may increase the risk of QT prolongation and ventricular arrhythmias.
Intervention:
Concomitant use of pimozide and sertraline hydrochloride is contraindicated [See Contraindications (4)].
Other Serotonergic Drugs
Clinical Impact:
The concomitant use of serotonergic drugs with sertraline hydrochloride increases the risk of serotonin syndrome.
Intervention:
Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of sertraline hydrochloride and/or concomitant serotonergic drugs [See Warnings and Precautions (5.2)].
Examples:
other SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort
Drugs that Interfere with Hemostasis (antiplatelet agents and anticoagulants)
Clinical Impact:
The concurrent use of an antiplatelet agent or anticoagulant with sertraline hydrochloride may potentiate the risk of bleeding.
Intervention:
Inform patients of the increased risk of bleeding associated with the concomitant use of sertraline hydrochloride and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio [See Warnings and Precautions (5.3)].
Examples:
aspirin, clopidogrel, heparin, warfarin
Drugs Highly Bound to Plasma Protein
Clinical Impact:
Sertraline hydrochloride is highly bound to plasma protein. The concomitant use of sertraline hydrochloride with another drug that is highly bound to plasma protein may increase free concentrations of sertraline hydrochloride or other tightly-bound drugs in plasma [See Clinical Pharmacology (12.3)].
Intervention:
Monitor for adverse reactions and reduce dosage of sertraline hydrochloride or other protein-bound drugs as warranted.
Examples:
warfarin
Drugs Metabolized by CYP2D6
Clinical Impact:
Sertraline hydrochloride is a CYP2D6 inhibitor [See Clinical Pharmacology (12.3)]. The concomitant use of sertraline hydrochloride with a CYP2D6 substrate may increase the exposure of the CYP2D6 substrate.
Intervention:
Decrease the dosage of a CYP2D6 substrate if needed with concomitant sertraline hydrochloride use. Conversely, an increase in dosage of a CYP2D6 substrate may be needed if sertraline hydrochloride is discontinued.
Examples:
propafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, thoridazine, tolterodine, venlafaxine
Phenytoin
Clinical Impact:
Phenytoin is a narrow therapeutic index drug. Sertraline hydrochloride may increase phenytoin concentrations.
Intervention:
Monitor phenytoin levels when initiating or titrating sertraline hydrochloride. Reduce phenytoin dosage if needed.
Examples:
phenytoin, fosphenytoin


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function.
Drugs that may alter T4 and T3 serum transport - but FT4 concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin/Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens/Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non-Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4 . Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ³ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias
and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123 I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
AED  Co - administered
AED  Concentration
Topiramate  Concentration
Phenytoin
NCor25%increase a
48%decrease
Carbamazepine(CBZ)
NC
40%decrease
CBZepoxide b
NC 
            NE
Valproic acid
11%decrease
14%decrease
Phenobarbital
NC
            NE
Primidone
NC
           NE
Lamotrigine
NCatTPM dosesupto400  mg/day 
         13%decrease


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.11, 7.3)


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir ) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Do not exceed 40 mg atorvastatin daily


Table name:
Antacids and Sucralfate
Clinical Impact:
Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention:
Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen is not recommended.
Cholestyramine
Clinical Impact:
Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention:
Concomitant administration of cholestyramine with naproxenis not recommended.
Probenecid
Clinical Impact:
Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention:
Patients simultaneously receiving naproxen and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact:
Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention:
Patients simultaneously receiving naproxen and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
↓= Decreased (induces lamotrigine glucuronidation).
↑= Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine Decreased lamotrigine concentrations approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? carbamazepine epoxide May increase carbamazepine epoxide levels.
Lopinavir/ritonavir ↓ lamotrigine Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir ↓ lamotrigine Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine Increased lamotrigine concentrations slightly more than 2-fold.
? valproate There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.


Table name:
AED Coadministered AED Concentration Topiramate Concentration
Phenytoin
NC or 25% increase Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
48% decrease


Carbamazepine (CBZ)
NC
40% decrease
CBZ epoxide Is not administered but is an active metabolite of carbamazepine.
NC
NE
Valproic acid
11% decrease
14% decrease
Phenobarbital
NC
NE
Primidone
NC
NE
Lamotrigine
NC at TPM doses up to 400 mg/day
13% decrease


Table name:
Interacting Drug Interaction
   Multivalent cation-containing products
   including antacids, metal cations or didanosine   
   Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)   
   Warfarin
   Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
   Antidiabetic agents
   Carefully monitor blood glucose (5.12, 7.3)


Table name:
Table II. Clinically significant drug interactions with theophylline*.
Drug Type of Interaction Effect†
 *    Refer to PRECAUTIONS, Drug Interactions for further information regarding table.
†    Average effect on steady state theophylline concentration or other clinical effect for pharmacologic
      interactions. Individual patients may experience larger changes in serum theophylline concentration
      than the value listed.
 Adenosine  Theophylline blocks adenosine
receptors.
 Higher doses of adenosine may be required to achieve
desired effect.
 Alcohol  A single large dose of alcohol (3
mL/kg of whiskey) decreases
theophylline clearance for up to
24 hours.
 30% increase
 Allopurinol  Decreases theophylline clearance
at allopurinol doses ≥600 mg/day.
 25% increase
 Aminoglutethimide  Increases theophylline clearance
by induction of microsomal
enzyme activity.
 25% decrease
 Carbamazepine  Similar to aminoglutethimide.  30% decrease
 Cimetidine  Decreases theophylline clearance
by inhibiting cytochrome P450
1A2.
 70% increase
 Ciprofloxacin  Similar to cimetidine.  40% increase
 Clarithromycin  Similar to erythromycin.  25% increase
 Diazepam  Benzodiazepines increase CNS
concentrations of adenosine, a
potent CNS depressant, while
theophylline blocks adenosine
receptors.
 Larger diazepam doses may be required to produce
desired level of sedation. Discontinuation of
theophylline without reduction of diazepam dose may
result in respiratory depression.
 Disulfiram  Decreases theophylline clearance
by inhibiting hydroxylation and
demethylation.
 50% increase
 Enoxacin  Similar to cimetidine.  300% increase
 Ephedrine  Synergistic CNS effects.  Increased frequency of nausea, nervousness, and
insomnia.
 Erythromycin  Erythromycin metabolite
decreases theophylline clearance
by inhibiting cytochrome P450
3A3.
 35% increase. Erythromycin steady-state serum
concentrations decrease by a similar amount.
 Estrogen  Estrogen containing oral
contraceptives decrease
theophylline clearance in a dose-
dependent fashion. The effect of
progesterone on theophylline
clearance is unknown.
 30% increase
 Flurazepam  Similar to diazepam.  Similar to diazepam.
 Fluvoxamine  Similar to cimetidine.  Similar to cimetidine
 Halothane  Halothane sensitizes the
myocardium to catecholamines,
theophylline increases release of
endogenous catecholamines.
 Increased risk of ventricular arrhythmias.
 Interferon, human
recombinant alpha-A
 Decreases theophylline clearance.  100% increase
 Isoproterenol (IV)  Increases theophylline clearance.  20% decrease
 Ketamine  Pharmacologic.  May lower theophylline seizure threshold.
 Lithium  Theophylline increases renal
lithium clearance.
 Lithium dose required to achieve a therapeutic serum
concentration increased an average of 60%.
 Lorazepam  Similar to diazepam.  Similar to diazepam.
 Methotrexate (MTX)  Decreases theophylline clearance.  20% increase after low dose MTX, higher dose MTX
may have a greater effect.
 Mexiletine  Similar to disulfiram.  80% increase
 Midazolam  Similar to diazepam.  Similar to diazepam.
 Moricizine  Increases theophylline clearance.  25% decrease
 Pancuronium  Theophylline may antagonize
non-depolarizing neuromuscular
blocking effects, possibly due to
phosphodiesterase inhibition.
 Larger dose of pancuronium may be required to
achieve neuromuscular blockade
 Pentoxifylline  Decreases theophylline clearance.  30% increase
 Phenobarbital (PB)  Similar to aminoglutethimide.  25% decrease after two weeks of concurrent PB.
 Phenytoin  Phenytoin increases theophylline
clearance by increasing
microsomal enzyme activity.
Theophylline decreases
phenytoin absorption.
 Serum theophylline and phenytoin concentrations
decrease about 40%.
 Propafenone  Decreases theophylline clearance
and pharmacologic interaction.
 40% increase. Beta2 blocking effect may decrease
efficacy of theophylline
 Propranolol  Similar to cimetidine and
pharmacologic interaction.
 100% increase. Beta2 blocking effect may decrease
efficacy of theophylline
 Rifampin  Increases theophylline clearance
by increasing cytochrome P450
1A2 and 3A3 activity.
 20-40% decrease
 St. John's Wort
(Hypericum
Perforatum)
 Decrease in theophylline plasma
concentrations.
 Higher doses of theophylline may be required to
achieve desired effect. Stopping St. John's Wort may
result in theophylline toxicity.
 Sulfinpyrazone  Increases theophylline clearance
by increasing demethylation and
hydroxylation. Decreases renal
clearance of theophylline.
 20% decrease
 Tacrine  Similar to cimetidine, also
increases renal clearance of
theophylline.
 90% increase
 Thiabendazole  Decreases theophylline clearance.  190% increase
 Ticlopidine  Decreases theophylline clearance.  60% increase
 Troleandomycin  Similar to erythromycin.  33-100% increase depending on troleandomycin dose.
 Verapamil  Similar to disulfiram.  20% increase


Table name:
Table 2: Rifabutin Interaction Studies
↑ indicates increase; ↓ indicates decrease; ↔ indicates no significant change
QD-once daily; BID-twice daily; TID – thrice daily
ND -No Data
AUC -Area under the Concentration vs. Time Curve; Cm a x -Maximum serum concentration
a compared to rifabutin 300 mg QD alone
b compared to historical control (fosamprenavir/ritonavir 700/100 mg BID)
c also taking zidovudine 500 mg QD
d compared to rifabutin 150 mg QD alone
e compared to rifabutin 300 mg QD alone
f data from a case report
g compared to voriconazole 200 mg BID alone
Coadministered  drug 
Dosing  regimen  of  coadministered  drug
Dosing  regimen  of  rifabutin
Study  population  ( n )
Effect  on  rifabutin
Effect  on  coadministered  drug
Recommendation
ANTIVIRALS 






Amprenavir 
1200 mg BID x 10 days
300 mg QD x 10 days
Healthy male subjects (6)
↑ AUC by 193%, ↑ Cm a x by 119%

Reduce rifabutin dose by at least 50%. Monitor closely for adverse reactions.
Delavirdine 
400 mg TID
300 mg QD
HIV-infected patients (7)
↑ AUC by 230%, ↑ Cm a x by 128%
↓ AUC by 80%, ↓ Cmax by 75%,
↓ Cm i n by 17%
CONTRAINDICATED
Didanosine 
167 or 250 mg BID x 12 days
300 or 600 mg QD x 1
HIV-infected patients (11)



Fosamprenavir/ ritonavir 
700 mg BID plus ritonavir 100 mg BID x 2 weeks
150 mg every other day x 2 weeks
Healthy subjects (15)
↔ AUCa ↓ Cm a x by 15%
↑ AUC by 35%b,
↑ Cm a x by 36%, ↑ Cm i n by 36%
Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with fosamprenavir/ritonavir combination.
Indinavir 
800 mg TID x 10 days
300 mg QD x 10 days
Healthy subjects (10)
↑ AUC by 173%, ↑ Cmax by 134%
↓ AUC by 34%, ↓ Cm a x by 25%, ↓ Cm i n by 39%
Reduce rifabutin dose by 50%, and increase indinavir dose from 800 mg to 1000 mg TID.
Lopinavir/
ritonavir 
400/100 mg BID x 20 days
150 mg QD x 10 days
Healthy subjects (14)
↑ AUC by 203%c
↓ Cm a x by 112%

Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with lopinavir/ritonavir combination. Monitor closely for adverse reactions. Reduce rifabutin dosage further, as needed.
Saquinavir/ ritonavir 
1000/100 mg BID x 14 or 22 days
150 mg every 3 days X 21 to 22 days
Healthy subjects
↑ AUC by 53% d ↑ Cm a x by 88% (n=11)
↓ AUC by 13%, ↓ Cm a x by 15%, (n=19)
Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with saquinavir/ritonavir combination. Monitor closely for adverse reactions.
Ritonavir 
500 mg BID x 10 days
150 mg QD x 16 days
Healthy subjects (5)
↑ AUC by 300%, ↑ Cm a x by 150%
ND
Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with lopinavir/ritonavir combination. Monitor closely for adverse reactions. Reduce rifabutin dosage further, as needed.
Tipranavir/ ritonavir 
500/200 BID X 15 doses
150 mg single dose
Healthy subjects (20)
↑ AUC by 190%, ↑ Cm a x by 70%

Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with tipranavir/ritonavir combination. Monitor closely for adverse reactions. Reduce rifabutin dosage further, as needed.
Nelfinavir 
1250 mg BID x 7 to 8 days
150 mg QD x 8 days
HIV-infected patients (11)
↑ AUC by 83%,e ↑ Cm a x by 19%

Reduce rifabutin dose by 50% (to 150 mg QD) and increase the nelfinavir dose to 1250 mg BID
Zidovudine 
100 or 200 mg q4h
300 or 450 mg QD
HIV-infected patients (16)

↓ AUC by 32%, ↓ Cm a x by 48%
Because zidovudine levels remained within the therapeutic range during coadministration of rifabutin, dosage adjustments are not necessary.
ANTIFUNGALS 



Fluconazole 
200 mg QD x 2 weeks
300 mg QD x 2 weeks
HIV-infected patients (12)
↑ AUC by 82%, ↑ Cm a x by 88%

Monitor for rifabutin associated adverse events. Reduce rifabutin dose or suspend rifabutin use if toxicity is suspected.
Posaconazole 
200 mg QD x 10 days
300 mg QD x 17 days
Healthy subjects (8)
↑ AUC by 72%, ↑ Cm a x by 31%
↓ AUC by 49%, ↓ Cm a x by 43%
If co-administration of these two drugs cannot be avoided, patients should be monitored for adverse events associated with rifabutin administration, and lack of posaconazole efficacy.
Itraconazole 
200 mg QD
300 mg QD
HIV-Infected patients (6)
f
↓ AUC by 70%, ↓ Cm a x by 75%
If co-administration of these two drugs cannot be avoided, patients should be monitored for adverse events associated with rifabutin administration, and lack of itraconazole efficacy. In a separate study, one case of uveitis was associated with increased serum rifabutin levels following coadministration of rifabutin (300 mg QD) with itraconazole (600 to 900 mg QD).
Voriconazole 
400 mg BID x 7 days (maintenance dose)
300 mg QD x 7 days
Healthy male subjects (12)
↑ AUC by 331%, ↑ Cm a x by 195%
↑ AUC by ~100%,
↑ Cm a x by ~100%g
CONTRAINDICATED
ANTI - PCP  ( Pneumocystis  carinii  pneumonia



Dapsone 
50 mg QD
300 mg QD
HIV-infected patients (16)
ND
↓ AUC by 27 to 40%

Sulfamethoxazole-Trimethoprim 
800/160 mg
300 mg QD
HIV-infected patients (12)

↓ AUC by 15 to 20%

ANTI - MAC  ( Mycobacterium  avium  intracellulare  complex
Azithromycin 
500 mg QD x 1 day, then 250 mg QD x 9 days
300 mg QD
Healthy subjects (6)



Clarithromycin 
500 mg BID
300 mg QD
HIV-infected patients (12)
↑ AUC by 75%
↓ AUC by 50%
Monitor for rifabutin associated adverse events. Reduce dose or suspend use of rifabutin if toxicity is suspected. Alternative treatment for clarithromycin should be considered when treating patients receiving rifabutin
ANTI - TB  ( Tuberculosis
Ethambutol 
1200 mg
300 mg QD X 7 days
Healthy subjects (10)
ND


Isoniazid 
300 mg
300 mg QD X 7 days
Healthy subjects (6)
ND


OTHER 
Methadone 
20 to 100 mg QD
300 mg QD X 13 days
HIV-infected patients (24)
ND


Ethinylestradiol (EE)/ Norethindrone (NE) 
35 mg EE / 1 mg NE X 21 days
300 mg QD X 10 days
Healthy female subjects (22)
ND
EE: ↓ AUC by 35%,
↓ Cmax by 20% NE: ↓ AUC by 46%
Patients should be advised to use additional or alternative methods of contraception.
Theophylline 
5 mg/kg
300 mg X 14 days
Healthy subjects (11)
ND




Table name:
Figure 1: Effect of interacting drugs on the pharmacokinetics of venlafaxine and active metabolite O-desmethylvenlafaxine (ODV).


Table name:
Table 6: Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology (12.3)]
Drug/Drug Class
(Mechanism of Interaction by the Drug)
Voriconazole Plasma Exposure
(Cmax and AUCτ after 200 mg q12h)
Recommendations for Voriconazole Dosage Adjustment/Comments
RifampinResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg q12h voriconazole to healthy subjects and Rifabutin
(CYP450 Induction)
Significantly Reduced Contraindicated
Efavirenz (400 mg q24h) Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects
(CYP450 Induction)
Significantly Reduced Contraindicated
Efavirenz (300 mg q24h)
(CYP450 Induction)
Slight Decrease in AUC τ When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h) (CYP450 Induction)

Low-dose Ritonavir (100 mg q12h) (CYP450 Induction)
Significantly Reduced

Reduced
Contraindicated

Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Carbamazepine
(CYP450 Induction)
Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction Contraindicated
Long Acting Barbiturates
(CYP450 Induction)
Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction Contraindicated
Phenytoin
(CYP450 Induction)
Significantly Reduced Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg)
St. John's Wort
(CYP450 inducer; P-gp inducer)
Significantly Reduced Contraindicated
Oral Contraceptives
containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)
Increased Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole (CYP2C9, CYP2C19 and CYP3A4 Inhibition) Significantly Increased Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole.
Other HIV Protease Inhibitors
(CYP3A4 Inhibition)
In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure

In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)
No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir

Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors
(CYP3A4 Inhibition or CYP450 Induction)
In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure)

A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs
(Decreased Plasma Exposure)
Frequent monitoring for adverse events and toxicity related to voriconazole



Careful assessment of voriconazole effectiveness


Table name:
Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s)
Recommendation
Comments
Tizanidine
Contraindicated
Concomitant administration of tizanidine and ciprofloxacin  is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2) ].
Theophylline
Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)
Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions (5.9) ].
Drugs Known to Prolong QT Interval
Avoid Use
 
Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see  Warnings and Precautions (5.11) and Use in Specific Populations (8.5) ].
Oral antidiabetic drugs
Use with caution Glucose-lowering effect potentiated
Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs [see Adverse Reactions (6.1) ].
Phenytoin
Use with caution Altered serum levels of phenytoin
(increased and decreased)
 
To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin with phenytoin.
Cyclosporine
Use with caution (transient elevations in serum creatinine)
Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs
Use with caution (Increase in anticoagulant effect)
The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate
Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels
Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole
Use with caution
Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin [see Warnings and Precautions (5.16) ].
Clozapine
Use with caution
Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs
Use with caution
Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil
Use with caution Two-fold increase in exposure
Monitor for sildenafil toxicity [see Clinical Pharmacology (12.3) ].
Duloxetine
Avoid Use
Five-fold increase in duloxetine exposure
If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives
Use with caution Reduced clearance resulting in elevated levels and prolongation
of serum half-life
Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx® (didanosine) chewable/ buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)
Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2.4) ].
Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid
Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)
Potentiation of ciprofloxacin toxicity may occur.


Table name:
Interacting Drug Interaction
Theophylline Serious and fatal reactions. Avoid concomitant use. Monitor serum level ( 7)
Warfarin Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding ( 7)
Antidiabetic agents Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose ( 7)
Phenytoin Monitor phenytoin level ( 7)
Methotrexate Monitor for methotrexate toxicity ( 7)
Cyclosporine May increase serum creatinine. Monitor serum creatinine ( 7)
Multivalent cation-containing products including antacids, metal cations or didanosine Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin ( 7)


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.10, 7.3)


Table name:
Interacting Drug Interaction
   Multivalent cation-containing products including antacids, metal cations or didanosine
   Absorption of levofloxacin is decreased when the tablet formulation  is taken within 2 hours of this product. (2.4, 7.1)
   Warfarin
   Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
   Antidiabetic agents
   Carefully monitor blood glucose (5.12, 7.3)


Table name:
Summary of antiepileptic drug (AED) interactions with topiramate (7.1).
AED co-administered AED Concentration Topiramate Concentration
Phenytoin NC or 25% increasePlasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. 48% decrease
Carbamazaepine (CBZ) NC 40% decrease
CBZ epoxideIs not administered but is an active metabolite of carbamazepine NC NE
Valproic acid 11% decrease 14% decrease
Phenobarbital NC NE
Primidone NC NE
Lamotrigine NC at TPM doses up to 400mg/day 13% decrease


Table name:
Table 4: Clinically Relevant Interactions Affecting Omeprazole When Co-Administered with Other Drugs
CYP2C19 or CYP3A4 Inducers
Clinical Impact:
Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology (12.3)].
Intervention:
St. John’s Wort, rifampin: Avoid concomitant use with omeprazole [see Warnings and Precautions (5.9)].
Ritonavir-containing products: see prescribing information for specific drugs.
CYP2C19 or CYP3A4 Inhibitors
Clinical Impact:
Increased exposure of omeprazole [see Clinical Pharmacology (12.3)].
Intervention:
Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered.
 
See prescribing information for voriconazole.


Table name:
Interacting Drug Interaction
Theophylline Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin Monitor phenytoin level (7)
Methotrexate Monitor for methotrexate toxicity (7)
Cyclosporine May increase serum creatinine. Monitor serum creatinine (7)
Multivalent cation-containing products including antacids, metal cations or didanosine Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin (7)


Table name:
Table 18. Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug Dosing Schedule Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio Change relative to reference ) Risperidone Dose Recommendation
Coadministered Drug Risperidone AUC Cmax
Enzyme (CYP2D6) Inhibitors
Fluoxetine 20 mg/day 2 mg or
3 mg twice daily
1.4 1.5 Reevaluate dosing. Do not exceed 8 mg/day
Paroxetine 10 mg/day 4 mg/day 1.3 -- Reevaluate dosing. Do not exceed 8 mg/day
20 mg/day 4 mg/day 1.6 --
40 mg/day - 4 mg/day 1.8 --
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine 573 ± 168 mg/day 3 mg twice daily 0.51 0.55 Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine 150 mg twice daily 1 mg single dose 1.2 1.4 Dose adjustment not needed
Cimetidine 400 mg twice daily 1 mg single dose 1.1 1.3 Dose adjustment not needed
Erythromycin 500 mg four times daily 1 mg single dose 1.1 0.94 Dose adjustment not needed
Other Drugs
Amitriptyline 50 mg twice daily 3 mg twice daily 1.2 1.1 Dose adjustment not needed


Table name:
Drugs that Affect Renal Function A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDS], COX-2 inhibitors may impair the excretion of digoxin.
Antiarrthymics Dofetilide Concomitant administration with digoxin was associated with a higher rate of torsades de pointes
Sotalol Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
Dronedarone Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone Analog Teriparatide Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement Thyroid Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics Epinephrine
Norepinephrine     
Dopamine
Can increase the risk of cardiac arrhythmias
Neuromuscular Blocking Agents      Succinylcholine May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.
Supplements Calcium If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
↓= Decreased (induces lamotrigine glucuronidation).
↑= Increased (inhibits lamotrigine glucuronidation).
?= Conflicting data.
Concomitant Drug
Effect on Concentration of 
Lamotrigine or Concomitant Drug
Clinical Comment
Estrogen-containing oral 
contraceptive preparations containing 
30 mcg ethinylestradiol and 
150 mcg levonorgestrel 
↓ lamotrigine 



↓ levonorgestrel 
Decreased lamotrigine levels approximately 50%. 



Decrease in levonorgestrel component by 19%. 
Carbamazepine (CBZ) and CBZ epoxide 
↓ lamotrigine 



? CBZ epoxide 
Addition of carbamazepine decreases lamotrigine 
concentration approximately 40%. 


May increase CBZ epoxide levels 
Phenobarbital/Primidone 
↓ lamotrigine 
Decreased lamotrigine concentration approximately 40%. 
Phenytoin (PHT) 
↓ lamotrigine 
Decreased lamotrigine concentration approximately 40%. 
Rifampin 
↓ lamotrigine 
Decreased lamotrigine AUC approximately 40%. 
Valproate 
↑ lamotrigine  


? valproate 
Increased lamotrigine concentrations slightly
more than 2-fold. 

Decreased valproate concentrations an average of
25% over a 3-week period then stabilized in healthy
volunteers; no change in controlled clinical trials in
epilepsy patients. 


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Grapefruit juice Avoid grapefruit juice


Table name:
Antiarrhythmics Dofetilide Concomitant administration with digoxin was associated with a higher rate of torsades de pointes.
Moricizine Reported to increase PR interval and QRS duration. There are reports of first degree atrioventricular block or bundle branch block developing with digitalis administration. The known effects of moricizine on calcium conductance may explain the effects on atrioventricular node conduction.
Sotalol Proarrhythmic events even more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving dioxin.
Parathyroid Hormone Analog Teriparatide Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid Supplement Thyroid Treatment of hyperthyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics Epinepherine Can increase the risk of cardiac arrhythmias.
Norepinephrine
Dopamine
Neuromuscular Blocking Agents Succinylcholine May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.
Supplements Calcium If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers Additive effects on AV node conduction can result in complete heart block.


Table name:
  Drug/Drug Class (Mechanism of Interaction by Voriconazole)   Drug Plasma Exposure
(Cmax and AUCτ)
  Recommendations for Drug Dosage Adjustment/Comments
 Sirolimus*
(CYP3A4 Inhibition)
 Significantly Increased   Contraindicated
 Rifabutin*
(CYP3A4 Inhibition)
 Significantly Increased   Contraindicated
 Efavirenz (400 mg q 24h)**
(CYP3A4 Inhibition)
Efavirenz (300 mg q 24h) ** (CYP3A4 Inhibition)
 Significantly Increased Slight decrease in AUCt   Contraindicated When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
 High-dose Ritonavir (400 mg q12h)**(CYP3A4 Inhibition) Low-dose Ritonavir (100 mg q12h)**  No Significant Effect of Voriconazole on Ritonavir Cmax or AUCτ Slight Decrease in Ritonavir Cmax and AUCτ   Contraindicated because of significant reduction of voriconazole Cmax and AUCτ
 Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole Cmax and AUCτ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
 Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (CYP3A4 Inhibition)  Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased   Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
 Ergot Alkaloids
(CYP450 Inhibition)
 Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased   Contraindicated
 Cyclosporine*
(CYP3A4 Inhibition)
 AUCτ Significantly Increased; No Significant Effect on Cmax  When initiating therapy with voriconazole in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When voriconazole is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
 Methadone***
(CYP3A4 Inhibition)
 Increased  Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
 Fentanyl
(CYP3A4 Inhibition)
 Increased  Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see DRUG INTERACTIONS (7)]
 Alfentanil
(CYP3A4 Inhibition)
 Significantly Increased  Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with voriconazole. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [see DRUG INTERACTIONS (7)].
 Oxycodone
(CYP3A4 Inhibition)
 Significantly Increased  Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see DRUG INTERACTIONS (7)].
 NSAIDs**** including ibuprofen and diclofenac (CYP2C9 Inhibition)  Increased  Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed. [see DRUG INTERACTIONS (7)].
 Tacrolimus* (CYP3A4 Inhibition)  Significantly Increased  When initiating therapy with voriconazole in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazole is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
 Phenytoin* (CYP2C9 Inhibition)  Significantly Increased  Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
 Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)**  Increased  Monitoring for adverse events related to oral contraceptives is recommended during coadministration.
 Warfarin* (CYP2C9 Inhibition)  Prothrombin Time Significantly Increased  Monitor PT or other suitable anticoagulation tests. Adjustment of warfarin dosage may be needed.
 Omeprazole* (CYP2C19/3A4 Inhibition)  Significantly Increased  When initiating therapy with voriconazole in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
 Other HIV Protease Inhibitors (CYP3A4 Inhibition)   In Vivo Studies Showed No Significant Effects on Indinavir Exposure  No dosage adjustment for indinavir when coadministered with voriconazole tablets
    In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)  Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors
 Other NNRTIs***** (CYP3A4 Inhibition)  A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure)  Frequent monitoring for adverse events and toxicity related to NNRTI
 Benzodiazepines (CYP3A4 Inhibition)   In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)  Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.
 HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition)   In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)  Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
 Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition)   In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)  Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
 Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition)  Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased  Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
 Vinca Alkaloids (CYP3A4 Inhibition)  Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased  Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed.
 Everolimus (CYP3A4 Inhibition)  Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased  Concomitant administration of voriconazole and everolimus is not recommended


Table name:
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine Decreased lamotrigine levels approximately 50%.
↓levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? CBZ epoxide May increase CBZ epoxide levels
Phenobarbital/Primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT) ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine Increased lamotrigine concentrations slightly more than 2-fold.
? valproate Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
Factors
Dosage  Adjustments  for  Aripiprazole  Tablets
Known CYP2D6 Poor Metabolizers
Administer half of usual dose
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors
Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors
Administer half of usual dose
Strong CYP2D6 and CYP3A4
inhibitors
Administer a quarter of usual dose
Strong CYP3A4 inducers
Double usual dose over 1 to 2 weeks


Table name:
NA = Not available/reported
Digoxin concentrations increased greater than 50%
   Digoxin Serum   
Concentration Increase
   Digoxin AUC Increase Recommendations
Amiodarone 70% NA Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring.
Captopril 58% 39%
Clarithromycin NA 70%
Dronedarone NA 150%
Gentamicin 129-212% NA
Erythromycin 100% NA
Itraconazole 80% NA
Lapatinib NA 180%
Propafenone NA 60-270%
Quinidine 100% NA
Ranolazine 50% NA
Ritonavir NA 86%
Telaprevir 50% 85%
Tetracycline 100% NA
Verapamil 50-75% NA
Digoxin concentrations increased less than 50%
Atorvastatin 22% 15% Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring.
Carvedilol 16% 14%
Conivaptan 33% 43%
Diltiazem 20% NA
Indomethacin 40% NA
Nefazodone 27% 15%
Nifedipine 45% NA
Propantheline 24% 24%
Quinine NA 33%
Rabeprazole 29% 19%
Saquinavir 27% 49%
Spironolactone      25% NA
Telmisartan 20-49% NA
Ticagrelor 31% 28%
Tolvaptan 30% 20%
Trimethoprim 22-28% NA
Digoxin concentrations increased, but magnitude is unclear
Alprazolam, azithromycin, cyclosporine, diclofenac, diphenoxylate, epoprostenol, esomeprazole, ibuprofen, ketoconazole, lansoprazole, metformin, omeprazole Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin concentrations decreased
Acarbose, activated charcoal, albuterol, antacids, certain cancer chemotherapy or radiation therapy, cholestyramine, colestipol, extenatide, kaolin-pectin, meals high in bran, metoclopramide, miglitol, neomycin, penicillamine, phenytoin, rifampin, St. John’s Wort, sucralfate and sulfasalazine Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20-40% as necessary.


Table name:
Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin Tablets, USP
Drug(s) Recommendation Comments
Tizanidine Contraindicated Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)]
Theophylline Avoid Use
(Plasma Exposure Likely to be Increased and Prolonged)
Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate. [See Warnings and Precautions (5.6).]
Drugs Known to Prolong QT Interval Avoid Use Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.10) and Use in
Specific Populations (8.5)].
Oral antidiabetic drugs Use with caution Glucose-lowering effect potentiated Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs. [See Adverse Reactions (6.1).]
Phenytoin Use with caution Altered serum levels of phenytoin (increased and decreased) To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin with phenytoin.
Cyclosporine Use with caution (transient elevations in serum creatinine) Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs Use with caution (Increase in anticoagulant effect) The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole Use with caution Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with Ciprofloxacin [see Warnings and Precautions (5.15)].
Clozapine Use with caution Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs Use with caution Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil Use with caution Two-fold increase in exposure Monitor for sildenafil toxicity (see Pharmacokinetics 12.3).
Duloxetine Avoid Use
Five-fold increase in duloxetine exposure
If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin Tablets, USP
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx®
(didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)
Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration. (2)].
Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid
Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)
Potentiation of ciprofloxacin toxicity may occur.


Table name:
Classes of Drug    
also: other medications affecting blood elements which may modify hemostasis dietary deficiencies prolonged hot weather unreliable PT/INR determinations
   5-lipoxygenase Inhibitor    Antiplatelet Drugs/Effects    Leukotriene Receptor Antagonist
   Adrenergic Stimulants, Central    Antithyroid Drugs    Monoamine Oxidase Inhibitors
   Alcohol Abuse Reduction    Beta-Adrenergic Blockers    Narcotics, prolonged
       Preparations    Cholelitholytic Agents    Nonsteroidal Anti-
   Analgesics    Diabetes Agents, Oral          Inflammatory Agents
   Anesthetics, Inhalation    Diuretics    Proton Pump Inhibitors
   Antiandrogen    Fungal Medications,     Psychostimulants
   Antiarrhythmics        Intravaginal, Systemic    Pyrazolones
   Antibiotics    Gastric Acidity and Peptic    Salicylates
      Aminoglycosides (oral)        Ulcer Agents    Selective Serotonin
      Cephalosporins, parenteral    Gastrointestinal          Reuptake Inhibitors
      Macrolides        Prokinetic Agents    Steroids, Adrenocortical
      Miscellaneous        Ulcerative Colitis Agents    Steroids, Anabolic (17-Alkyl
      Penicillins, intravenous,    Gout Treatment Agents           Testosterone Derivatives)
         high dose    Hemorrheologic Agents    Thrombolytics
      Quinolones (fluoroquinolones)    Hepatotoxic Drugs    Thyroid Drugs
      Sulfonamides, long acting    Hyperglycemic Agents    Tuberculosis Agents
      Tetracyclines    Hypertensive Emergency  Agents              Uricosuric Agents
   Anticoagulants    Hypnotics    Vaccines
   Anticonvulsants    Hypolipidemics    Vitamins
   Antidepressants       Bile Acid-Binding Resins
   Antimalarial Agents       Fibric Acid Derivatives
   Antineoplastics          HMG-CoA Reductase   Inhibitors
   Antiparasitic/Antimicrobials
Specific Drugs Reported    
   acetaminophen    fenoprofen    paroxetine
   alcoholIncreased and decreased PT/INR responses have been reported.    fluconazole    penicillin G, intravenous
   allopurinol    fluorouracil    pentoxifylline
   aminosalicylic acid    fluoxetine    phenylbutazone
   amiodarone HCl    flutamide    phenytoin
   argatroban    fluvastatin    piperacillin
   aspirin    fluvoxamine    piroxicam
   atenolol    gefitinib    pravastatin
   atorvastatin    gemfibrozil    prednisone
   azithromycin    glucagon    propafenone
   bivalirudin    halothane    propoxyphene
   capecitabine    heparin    propranolol
   cefamandole    ibuprofen    propylthiouracil
   cefazolin    ifosfamide    quinidine
   cefoperazone    indomethacin    quinine
   cefotetan    influenza virus vaccine    rabeprazole
   cefoxitin    itraconazole    ranitidine
   ceftriaxone    ketoprofen    rofecoxib
   celecoxib    ketorolac    sertraline
   cerivastatin    lansoprazole    simvastatin
   chenodiol    lepirudin    stanozolol
   chloramphenicol    levamisole    streptokinase
   chloral hydrate    levofloxacin    sulfamethizole
   chlorpropamide    levothyroxine    sulfamethoxazole
   cholestyramine    liothyronine    sulfinpyrazone
   cimetidine    lovastatin    sulfisoxazole
   ciprofloxacin    mefenamic acid    sulindac
   cisapride    methimazole    tamoxifen
   clarithromycin    methyldopa    tetracycline
   clofibrate    methylphenidate    thyroid
   warfarin sodium overdose    methylsalicylate ointment (topical)    ticarcillin
   cyclophosphamide    metronidazole    ticlopidine
   danazol    miconazole     tissue plasminogen
   dextran    (intravaginal, oral, systemic)    activator (t-PA)
   dextrothyroxine    moricizine hydrochloride    tolbutamide
   diazoxide    nalidixic acid    tramadol
   diclofenac    naproxen    trimethoprim/sulfamethoxazole
   dicumarol    neomycin    urokinase
   diflunisal    norfloxacin    valdecoxib
   disulfiram    ofloxacin    valproate
   doxycycline    olsalazine    vitamin E
   erythromycin    omeprazole    zafirlukast
   esomeprazole    oxandrolone    zileuton
   ethacrynic acid    oxaprozin
   ezetimibe    oxymetholone
   fenofibrate    pantoprazole


Table name:
Interacting Drug Interaction
Multivalent cation - containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.12, 7.3)


Table name:
Bleeding times
Clinical Impact: Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention: This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact: The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention: Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with NAPRELAN be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact: Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention: This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid are determined.


Table name:
Table 4. Sevelamer Drug Interactions
Oral drugs for which sevelamer did not alter the pharmacokinetics when administered concomitantly
Digoxin
Enalapril
Iron
Metoprolol
Warfarin
Oral drugs that have demonstrated interaction with sevelamer and are to be dosed separately from Renvela

Ciprofloxacin
Mycophenolate mofetil
Dosing Recommendations
Take at least 2 hours before or 6 hours after sevelamer
Take at least 2 hours before sevelamer


Table name:
Table 4: Drugs Having Clinically Important Interactions with Amphetamines
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact Concomitant use of MAOIs and CNS stimulants can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure.
Intervention Do not administer MAS-ER Capsules concomitantly or within 14 days after discontinuing MAOI [see CONTRAINDICATIONS (4) and WARNINGS AND PRECAUTIONS (5.6)].
Examples selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue
Serotonergic Drugs
Clinical Impact The concomitant use of MAS-ER Capsules and serotonergic drugs increases the risk of serotonin syndrome.
Intervention Initiate with lower doses and monitor patients for signs and symptoms of serotonin syndrome, particularly during MAS-ER Capsules initiation or dosage increase. If serotonin syndrome occurs, discontinue MAS-ER Capsules and the concomitant serotonergic drug(s) [see WARNINGS AND PRECAUTIONS (5.6)].
Examples selective serotonin reuptake inhibitors (SSRI), serotonin norepinephrine reuptake inhibitors (SNRI), triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John's Wort
CYP2D6 Inhibitors
Clinical Impact The concomitant use of MAS-ER Capsules and CYP2D6 inhibitors may increase the exposure of MAS-ER Capsules compared to the use of the drug alone and increase the risk of serotonin syndrome.
Intervention Initiate with lower doses and monitor patients for signs and symptoms of serotonin syndrome particularly during MAS-ER Capsules initiation and after a dosage increase. If serotonin syndrome occurs, discontinue MAS-ER Capsules and the CYP2D6 inhibitor [see WARNINGS AND PRECAUTIONS (5.6) and OVERDOSAGE (10)].
Examples paroxetine and fluoxetine (also serotonergic drugs), quinidine, ritonavir
Alkalinizing Agents
Clinical Impact Increase blood levels and potentiate the action of amphetamine.
Intervention Co-administration of MAS-ER Capsules and gastrointestinal or urinary alkalinizing agents should be avoided.
Examples Gastrointestinal alkalinizing agents (e.g., sodium bicarbonate). Urinary alkalinizing agents (e.g. acetazolamide, some thiazides).
Acidifying Agents
Clinical Impact Lower blood levels and efficacy of amphetamines.
Intervention Increase dose based on clinical response.
Examples Gastrointestinal acidifying agents (e.g., guanethidine, reserpine, glutamic acid HCl, ascorbic acid).
Urinary acidifying agents (e.g., ammonium chloride, sodium acid phosphate, methenamine salts).
Tricyclic Antidepressants
Clinical Impact May enhance the activity of tricyclic or sympathomimetic agents causing striking and sustained increases in the concentration of d-amphetamine in the brain; cardiovascular effects can be potentiated.
Intervention Monitor frequently and adjust or use alternative therapy based on clinical response.
Examples desipramine, protriptyline
Proton Pump Inhibitors
Clinical Impact Time to maximum concentration (Tmax) of amphetamine is decreased compared to when administered alone.
Intervention Monitor patients for changes in clinical effect and adjust therapy based on clinical response.
Examples omeprazole


Table name:
Table 3. Comparison of Clopidogrel Active Metabolite Exposure and Platelet Inhibition with and without Proton Pump Inhibitors, Omeprazole and Pantoprazole
 
% Change from Plavix (300 mg/75 mg) alone
Plavix plus Cmax (ng/mL) AUC Platelet InhibitionInhibition of platelet aggregation with 5 mcM ADP (%)
Day 1 Day 5 Day 1 Day 5AUC at Day 5 is AUC0-24 Day 1 Day 5
OmeprazoleSimilar results seen when Plavix and omeprazole were administered 12 hours apart. 80 mg ↓46% ↓42% ↓45% ↓40% ↓39% ↓21%
Pantoprazole 80 mg ↓24% ↓28% ↓20% ↓14% ↓15% ↓11%


Table name:
Table 5. Drugs That May Decrease Conversion of T4 to T3
Potential impact: Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased.
Drug or Drug Class Effect
Beta-adrenergic antagonists
(e.g., Propranolol > 160 mg/day)
In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change, TSH levels remain normal, and patients are clinically euthyroid. Actions of particular beta-adrenergic antagonists may be impaired when a hypothyroid patient is converted to the euthyroid state.
Glucocorticoids
(e.g., Dexamethasone > 4 mg/day)
Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (See above).
Other drugs:
Amiodarone
Amiodarone inhibits peripheral conversion of levothyroxine (T4) to triiodothyronine (T3) and may cause isolated biochemical changes (increase in serum free-T4, and decreased or normal free-T3) in clinically euthyroid patients.


Table name:
Interacting Agents  Prescribing Recommendations 
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone  Avoid simvastatin 
Gemfibrozil, cyclosporine, danazol  Do not exceed 10 mg simvastatin daily 
Amiodarone, verapamil  Do not exceed 20 mg simvastatin daily 
Grapefruit juice  Avoid large quantities of grapefruit juice (>1 quart daily) 


Table name:
Drug Description
Corticosteroids Decreases plasma salicylate level; Tapering doses of steroids may promote salicylism
Ammonium Sulfate Increases plasma salicylate level


Table name:
Table 9. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class:
Drug Name
Effect on Concentration of Lopinavir or Concomitant Drug Clinical Comment
HIV-1 Antiviral Agents
Non-nucleoside Reverse Transcriptase Inhibitors:
efavirenz*,
nevirapine*
↓ lopinavir KALETRA dose increase is recommended in all patients [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
Increasing the dose of KALETRA tablets to 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) twice daily co-administered with efavirenz resulted in similar lopinavir concentrations compared to KALETRA tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz.
Increasing the dose of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice daily co-administered with efavirenz resulted in significantly higher lopinavir plasma concentrations compared to KALETRA tablets 400/100 mg twice daily without efavirenz.
KALETRA should not be administered once daily in combination with efavirenz or nevirapine
[see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
Non-nucleoside Reverse Transcriptase Inhibitor:
delavirdine
↑ lopinavir Appropriate doses of the combination with respect to safety and efficacy have not been established.
Nucleoside Reverse Transcriptase Inhibitor:
didanosine
  KALETRA tablets can be administered simultaneously with didanosine without food.
For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food).
Nucleoside Reverse Transcriptase Inhibitor:
tenofovir
↑ tenofovir KALETRA increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir.
Nucleoside Reverse Transcriptase Inhibitor:
abacavir
zidovudine
↓ abacavir
↓ zidovudine
KALETRA induces glucuronidation; therefore, KALETRA has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown.
HIV-1 Protease Inhibitor:
amprenavir*
↑ amprenavir
↓ lopinavir
KALETRA should not be administered once daily in combination with amprenavir
[see Dosage and Administration (2.1)].
HIV-1 Protease Inhibitor:
fosamprenavir/ritonavir
↓ amprenavir
↓ lopinavir
An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor:
indinavir*
↑ indinavir Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily [see Clinical Pharmacology (12.3)]. KALETRA once daily has not been studied in combination with indinavir.
HIV-1 Protease Inhibitor:
nelfinavir*
↑ nelfinavir
↑ M8 metabolite of nelfinavir
↓ lopinavir
KALETRA should not be administered once daily in combination with nelfinavir
[see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].

HIV-1 Protease Inhibitor:
ritonavir*
↑ lopinavir Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor:
saquinavir*
↑ saquinavir The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily.
KALETRA once daily has not been studied in combination with saquinavir.
HIV-1 Protease Inhibitor:
tipranavir
↓ lopinavir AUC and Cmin KALETRA should not be administered with tipranavir (500 mg twice daily) co-administered with ritonavir (200 mg twice daily).
HIV CCR5 – antagonist: maraviroc ↑ maraviroc Concurrent administration of maraviroc with KALETRA will increase plasma levels of maraviroc. When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for Selzentry® (maraviroc).
Other Agents
Antiarrhythmics:
amiodarone,
bepridil,
lidocaine (systemic), and
quinidine
↑ antiarrhythmics Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA.
Anticancer Agents:
vincristine,
vinblastine,
dasatinib,
nilotinib
↑ anticancer agents Concentrations of these drugs may be increased when co-administered with KALETRA resulting in the potential for increased adverse events usually associated with these anticancer agents.
For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when KALETRA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor.
A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as KALETRA. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions.
Anticoagulant:
warfarin
  Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants:
carbamazepine,
phenobarbital,
phenytoin
↓ lopinavir
↓ phenytoin
KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution.
KALETRA should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin.

In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA.
Antidepressant:
bupropion
↓ bupropion
↓ active metabolite,
hydroxybupropion
Concurrent administration of bupropion with KALETRA may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion.
Antidepressant:
trazodone
↑ trazodone Concomitant use of trazodone and KALETRA may increase concentrations of trazodone. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered.
Anti-infective:
clarithromycin
↑ clarithromycin For patients with renal impairment, the following dosage adjustments should be considered:
  • For patients with CLCR 30 to 60 mL/min the dose
    of clarithromycin should be reduced by 50%.
  • For patients with CLCR < 30 mL/min the dose
    of clarithromycin should be decreased by 75%.

No dose adjustment for patients with normal renal function is necessary.
Antifungals:
ketoconazole*,
itraconazole,
voriconazole
↑ ketoconazole
↑ itraconazole
↓ voriconazole
High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended.
Co-administration of voriconazole with KALETRA has not been studied. However, a study has been shown that administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%; therefore, co-administration of KALETRA and voriconazole may result in decreased voriconazole concentrations and the potential for decreased voriconazole effectiveness and should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Otherwise, alternative antifungal therapies should be considered in these patients.
Anti-gout:
colchicine
↑ colchicine Patients with renal or hepatic impairment should not be given colchicine with KALETRA.

Treatment of gout flares-co-administration of colchicine in patients on KALETRA:

0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days.

Prophylaxis of gout flares-co-administration of colchicine in patients on KALETRA:

If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.

If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.

Treatment of familial Mediterranean fever (FMF)-co-administration of colchicine in patients on KALETRA:

Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Antimycobacterial:
rifabutin*
↑ rifabutin and rifabutin metabolite Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary.
Antimycobacterial:
rifampin
↓ lopinavir May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents. A study evaluated combination of rifampin 600 mg once daily, with KALETRA 800/200 mg twice daily or KALETRA 400/100 mg + ritonavir 300 mg twice daily. Pharmacokinetic and safety results from this study do not allow for a dose recommendation. Nine subjects (28%) experienced a ≥ grade 2 increase in ALT/AST, of which seven (21%) prematurely discontinued study per protocol. Based on the study design, it is not possible to determine whether the frequency or magnitude of the ALT/AST elevations observed is higher than what would be seen with rifampin alone [see Clinical Pharmacology (12.3) for magnitude of interaction].
Antiparasitic:
atovaquone
↓ atovaquone Clinical significance is unknown; however, increase in atovaquone doses may be needed.
Benzodiazepines: parenterally administered midazolam ↑ midazolam Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, KALETRA should not be given with orally administered midazolam [see Contraindications (4)]. If KALETRA is coadministered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.
Calcium Channel Blockers, dihydropyridine:
e.g., felodipine,
nifedipine,
nicardipine
↑ dihydropyridine calcium channel blockers Caution is warranted and clinical monitoring of patients is recommended.
Contraceptive:
ethinyl estradiol*
↓ ethinyl estradiol Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended.
Corticosteroid:
dexamethasone

↓ lopinavir Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly.


disulfiram/metronidazole   KALETRA oral solution contains alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).
Endothelin receptor antagonists:
bosentan
↑ bosentan Co-administration of bosentan in patients on KALETRA:

In patients who have been receiving KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

Co-administration of KALETRA in patients on bosentan:

Discontinue use of bosentan at least 36 hours prior to initiation of KALETRA.

After at least 10 days following the initiation of KALETRA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
HMG-CoA Reductase Inhibitors:
atorvastatin
rosuvastatin
↑ atorvastatin
↑ rosuvastatin
Use lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin or fluvastatin in combination with KALETRA.
Immunosuppressants:
cyclosporine,
tacrolimus,
rapamycin
↑ immunosuppressants Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA.
Inhaled Steroid:
fluticasone
↑ fluticasone Concomitant use of fluticasone propionate and KALETRA may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during post-marketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Co-administration of fluticasone propionate and KALETRA is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effect.
Long-acting beta-adrenoceptor agonist:
salmeterol
↑ salmeterol Concurrent administration of salmeterol and KALETRA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Narcotic Analgesic:
methadone*
fentanyl
↓ methadone
↑ fentanyl
Dosage of methadone may need to be increased when co-administered with KALETRA.
Concentrations of fentanyl are expected to increase. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with KALETRA.
PDE5 inhibitors:
sildenafil,
tadalafil,
vardenafil
↑ sildenafil
↑ tadalafil
↑ vardenafil
Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs is expected to substantially increase their concentrations and may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection.

Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH):

Sildenafil (Revatio®) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with KALETRA [see Contraindications (4)].

The following dose adjustments are recommended for use of tadalafil (Adcirca®) with KALETRA:

Co-administration of ADCIRCA in patients on KALETRA:

In patients receiving KALETRA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Co-administration of KALETRA in patients on ADCIRCA:

Avoid use of ADCIRCA during the initiation of KALETRA. Stop ADCIRCA at least 24 hours prior to starting KALETRA. After at least one week following the initiation of KALETRA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Use of PDE5 inhibitors for erectile dysfunction:

It is recommended not to exceed the following doses:
  • Sildenafil: 25 mg every 48 hours
  • Tadalafil: 10 mg every 72 hours
  • Vardenafil: 2.5 mg every 72 hours

Use with increased monitoring for adverse events.
*   see Clinical Pharmacology (12.3) for Magnitude of Interaction.


Table name:
Table 25: Clinically Important Drug Interactions with ABILIFY:
Concomitant Drug Name or Drug Class Clinical Rationale Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) The concomitant use of ABILIFY with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of ABILIFY alone [see CLINICAL PHARMACOLOGY (12.3)]. With concomitant use of ABILIFY with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the ABILIFY dosage [see DOSAGE AND ADMINISTRATION (2.7)] .
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin) The concomitant use of ABILIFY and carbamazepine decreased the exposure of aripiprazole compared to the use of ABILIFY alone [see CLINICAL PHARMACOLOGY (12.3)] . With concomitant use of ABILIFY with a strong CYP3A4 inducer, consider increasing the ABILIFY dosage [see DOSAGE AND ADMINISTRATION (2.7)] .
Antihypertensive Drugs Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.8) ].
Benzodiazepines (e.g., lorazepam) The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.8) ] Monitor sedation and blood pressure. Adjust dose accordingly.


Table name:
Table 23: Clinically Important Drug Interactions with Aripiprazole:
Concomitant  Drug  Name  or  Drug  Class

Clinical  Rationale

Clinical  Recommendation

Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine)
The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone  [ see  CLINICAL  PHARMACOLOGY  ( 12 . 3 )].
With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage  [ see  DOSAGE  AND  ADMINISTRATION ( 2 . 7 )].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)
The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone  [ see  CLINICAL  PHARMACOLOGY  ( 12 . 3 )].
With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage  [ see  DOSAGE  AND  ADMINISTRATION ( 2 . 7 )].
Antihypertensive Drugs
Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.
Monitor blood pressure and adjust dose accordingly  [ see  WARNINGS  AND  PRECAUTIONS  ( 5 . 7 )].
Benzodiazepines (e.g., lorazepam)
The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepamalone  [ see  WARNINGS  AND  PRECAUTIONS  ( 5 . 7 )]
Monitor sedation and blood pressure. Adjust dose accordingly.



Table name:
Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s) Recommendation Comments
Tizanidine Contraindicated Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [ see Contraindications (4.2) ] .
Theophylline Avoid Use
(Plasma Exposure Likely to be
Increased and Prolonged)
Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [ s ee Warnings and Precautions (5.9) ] .
Drugs Known to
Prolong QT Interval
Avoid Use Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.11) and Use in Specific Populations (8.5) ].
Oral antidiabetic drugs Use with caution
Glucose-lowering effect potentiated
Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were coadministered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is coadministered with oral antidiabetic drugs [ s ee Adverse Reactions (6.1) ] .
Phenytoin Use with caution
Altered serum levels of phenytoin (increased and decreased)
To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after coadministration of ciprofloxacin with phenytoin.
Cyclosporine Use with caution
(transient elevations in serum creatinine)
Monitor renal function (in particular serum creatinine) when ciprofloxacin is coadministered with cyclosporine.
Anti-coagulant drugs Use with caution
(Increase in anticoagulant effect)
The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after coadministration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate Use with caution
Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels
Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole Use with caution Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after coadministration with ciprofloxacin [see Warnings and Precautions (5.16) ].
Clozapine Use with caution Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after coadministration with ciprofloxacin are advised.
NSAIDs Use with caution Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil Use with caution
Two-fold increase in exposure
Monitor for sildenafil toxicity [ s ee   C li n ic a l
Pha r m a c o l og y   ( 1 2 .3)].
Duloxetine Avoid Use
Five-fold increase in duloxetine exposure
If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine
Derivatives
Use with caution
Reduced clearance resulting in elevated levels and prolongation of serum half-life
Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate,
Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx®
(didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)
Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration  (2.4) ]. Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid Use with caution
(interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)
Potentiation of ciprofloxacin toxicity may occur.


Table name:
* Antacids may affect absorption of phenytoin.
† The induction potency of St. John's wort may vary widely based on preparation. 
Interacting Agent
Examples
Drugs that may increase phenytoin serum levels
Antiepileptic drugs
Ethosuximide, felbamate, oxcarbazepine, methsuximide, topiramate
Azoles
Fluconazole, ketoconazole, itraconazole, miconazole, voriconazole
Antineoplastic agents
Capecitabine, fluorouracil
Antidepressants
Fluoxetine, fluvoxamine, sertraline
Gastric acid reducing agents
H2 antagonists (cimetidine), omeprazole
Sulfonamides
Sulfamethizole, sulfaphenazole, sulfadiazine, sulfamethoxazole-trimethoprim
Other
Acute alcohol intake, amiodarone, chloramphenicol, chlordiazepoxide, disulfiram, estrogen, fluvastatin, isoniazid, methylphenidate, phenothiazines, salicylates, ticlopidine, tolbutamide, trazodone, warfarin
Drugs that may decrease phenytoin serum levels
Antacids*
Calcium carbonate, aluminum hydroxide, magnesium hydroxide
Prevention or Management: Phenytoin and antacids should not be taken at the same time of day
Antineoplastic agents usually in combination
Bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate
Antiviral agents
Fosamprenavir, nelfinavir, ritonavir
Antiepileptic drugs
Carbamazepine, vigabatrin
Other
Chronic alcohol abuse, diazepam, diazoxide, folic acid, reserpine, rifampin, St. John's wort, sucralfate, theophylline
Drugs that may either increase or decrease phenytoin serum levels
Antiepileptic drugs
Phenobarbital, valproate sodium, valproic acid


Table name:
CONCOMITANT DRUG CLINICAL EFFECT(S)
Amphetamines, cocaine, other sympathomimetic agents Additive hypertension, tachycardia, possibly cardiotoxicity
Atropine, scopolamine, antihistamines, other anticholinergic agents Additive or super-additive tachycardia, drowsiness
Amitriptyline, amoxapine, desipramine, other tricyclic antidepressants Additive tachycardia, hypertension, drowsiness
Barbiturates, benzodiazepines, ethanol, lithium, opioids, buspirone, antihistamines, muscle relaxants, other CNS depressants Additive drowsiness and CNS depression
Disulfiram A reversible hypomanic reaction was reported in a 28 y/o man who smoked marijuana; confirmed by dechallenge and rechallenge
Fluoxetine A 21 y/o female with depression and bulimia receiving 20 mg/day fluoxetine X 4 wks became hypomanic after smoking marijuana; symptoms resolved after 4 days
Antipyrine, barbiturates Decreased clearance of these agents, presumably via competitive inhibition of metabolism
Theophylline Increased theophylline metabolism reported with smoking of marijuana; effect similar to that following smoking tobacco


Table name:
Specific Drugs Reported
also: other medications affecting blood elements which may modify hemostasis
  dietary deficiencies
  prolonged hot weather
  unreliable PT/INR determinations
†Increased and decreased PT/INR responses have been reported.
acetaminophen
alcohol†
allopurinol
aminosalicylic acid
amiodarone HCl
argatroban
aspirin
atenolol
atorvastatin†
azithromycin
bivalirudin
capecitabine
cefamandole
cefazolin
cefoperazone
cefotetan
cefoxitin
ceftriaxone
celecoxib
cerivastatin
chenodiol
chloramphenicol
chloral hydrate†
chlorpropamide
cholestyramine†
cimetidine
ciprofloxacin
cisapride
clarithromycin
clofibrate
cyclophosphamide†
danazol
dextran
dextrothyroxine
diazoxide
diclofenac
dicumarol
diflunisal
disulfiram
doxycycline
erythromycin
esomeprazole
ethacrynic acid
ezetimibe
fenofibrate
fenoprofen
fluconazole
fluorouracil
fluoxetine
flutamide
fluvastatin
fluvoxamine
gefitinib
gemifibrozil
glucagon
halothane
heparin
ibuprofen
ifosfamide
indomethacin
influenza virus vaccine
itraconazole
ketoprofen
ketorolac
lansoprazole
lepirudin
levamisole
levofloxacin
levothyroxine
liothyronine
lovastatin
mefenamic acid
methimazole†
methyldopa
methylphenidate
methylsalicylate
  ointment (topical)
metronidazole
miconazole
  (intravaginal, oral,
    systemic)
moricizine
  hydrochloride†
nalidixic acid
naproxen
neomycin
norfloxacin
ofloxacin
olsalazine
omeprazole
oxandrolone
oxaprozin
oxymetholone
pantoprazole
paroxetine
penicillin G,
  intravenous
pentoxifylline
phenylbutazone
phenytoin†
piperacillin
piroxicam
pravastatin†
prednisone†
propafenone
propoxyphene
propranolol
propylthiouracil†
quinidine
quinine
rabeprazole
ranitidine†
rofecoxib
sertraline
simvastatin
stanozolol
streptokinase
sulfamethizole
sulfamethoxazole
sulfinpyrazone
sulfisoxazole
sulindac
tamoxifen
tetracycline
thyroid
ticarcillin
ticlopidine
tissue plasminogen
  activator (t-PA)
tolbutamide
tramadol
trimethoprim/
  sulfamethoxazole
urokinase
valdecoxib
valproate
vitamin E
warfarin overdose
zafirlukast
zileuton


Table name:

Figure 6: Mean Standing Systolic Blood Pressure Change from Baseline


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on
Concentration of Lamotrigine or Concomitant Drug
Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine Decreased lamotrigine concentrations approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? carbamazepine epoxide May increase carbamazepine epoxide levels.
 Lopinavir/ritonavir ↓ lamotrigine Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir ↓ lamotrigine Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine
Increased lamotrigine concentrations slightly more than 2-fold.
? valproate There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.


Table name:
Table 18Summary of Effect of Coadministered Drugs on Exposure to Active Moiety(Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients withSchizophrenia
*Change relative to reference
Coadministered Drug
Dosing Schedule
Effect on Active
Moiety
(Risperidone + 9-
Hydroxy-
Risperidone (Ratio*)
Risperidone Dose
Recommendation
Coadministered Drug
Risperidone
AUC
C max
Enzyme (CYP2D6) 
Inhibitors 
Fluoxetine 
20 mg/day
2 or 3 mg twice
daily
1.4
1.5
Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine 
10 mg/day
4 mg/day
1.3
-
Re-evaluate dosing. 
20 mg/day
4 mg/day
1.6
-
Do not exceed 8 mg/day
40 mg/day
4 mg/day
1.8
-
Enzyme (CYP3A/ 
PgP inducers) 
Carbamazepine 
573 ± 168 mg/day
3 mg twice daily
0.51
0.55
Titrate dose upwards.
Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) 
Inhibitors 
Ranitidine 
150 mg twice daily
1 mg single dose
1.2
1.4
Dose adjustment not
needed
Cimetidine 
400 mg twice daily
1 mg single dose
1.1
1.3
Dose adjustment not
needed
Erythromycin 
500 mg four times
daily
1 mg single dose
1.1
0.94
Dose adjustment not
needed
Other Drugs 
Amitriptyline 
50 mg twice daily
3 mg twice daily
1.2
1.1
Dose adjustment not
needed


Table name:
Coadministered Drug Dosing Schedule Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio*) Risperidone Dose Recommendation
Coadministered Drug Risperidone AUC Cmax  
Enzyme (CYP2D6) Inhibitors          
Fluoxetine 20 mg/day 2 or 3 mg twice daily 1.4 1.5 Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine 10 mg/day 4 mg/day 1.3 - Re-evaluate dosing. Do not exceed 8 mg/day
  20 mg/day 4 mg/day 1.6 -
  40 mg/day 4 mg/day 1.8 -
Enzyme (CYP3A/ PgP inducers) Inducers          
Carbamazepine 573 ± 168 mg/day 3 mg twice daily 0.51 0.55 Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors          
Ranitidine 150 mg twice daily 1 mg single dose 1.2 1.4 Dose adjustment not needed
Cimetidine 400 mg twice daily 1 mg single dose 1.1 1.3 Dose adjustment not needed
Erythromycin 500 mg four times daily 1 mg single dose 1.1 0.94 Dose adjustment not needed
Other Drugs          
Amitriptyline 50 mg twice daily 3 mg twice daily 1.2 1.1 Dose adjustment not needed


Table name:
Table 2: Clinically Significant Drug Interactions with diclofenac
Drugs That Interfere with Hemostasis
Clinical Impact:  Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case- control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:  Monitor patients with concomitant use of CAMBIA with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)]
Aspirin
Clinical Impact:  Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].
Intervention:  Concomitant use of CAMBIA and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)].
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-blockers
Clinical Impact:  NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta- blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:  During concomitant use of CAMBIA and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of CAMBIA and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)].
Diuretics
Clinical Impact:  Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:  During concomitant use of CAMBIA with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Clinical Impact:  The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:  During concomitant use of CAMBIA and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:  NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:  During concomitant use of CAMBIA and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:  Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:  During concomitant use of CAMBIA and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:  Concomitant use of CAMBIA and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:  During concomitant use of CAMBIA and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:  Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention:  The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:  Concomitant use of CAMBIA and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:  During concomitant use of NSAIDs and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Inhibitors of Cytochrome P450 2C9
Clinical Impact:  Diclofenac is metabolized predominantly by Cytochrome P-450 CYP2C9. Co- administration of medications that inhibit CYP2C9 may affect the pharmacokinetics of diclofenac [see Warnings and Precautions (12.3)]
Intervention:  During concomitant use of CAMBIA and drugs that inhibit CYP2C9, an increase in the duration between CAMBIA doses for subsequent migraine attacks may be necessary.


Table name:
Table 3: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 10 and 20 mg in BPH patients on stable alpha-blocker therapy with tamsulosin 0.4 or 0.8 mg daily (Study 2)
Vardenafil 10 mg
Placebo-subtracted
Vardenafil 20 mg
Placebo-subtracted
Standing SBP -4 (-6.8, -0.3) -4 (-6.8, -1.4)
Supine SBP -5 (-8.2, -0.8) -4 (-6.3, -1.8)


Table name:
Bleeding times
Clinical Impact: Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention: This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact: The administration of naproxen may result in increased urinary values for 17 ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention: Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact: Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention: This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.


Table name:
Bleeding times
Clinical Impact: Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention: This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact: The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention: Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact: Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention: This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.


Table name:
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitors (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Table 4 Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table 5 for Magnitude of Interaction.
Drug Name Effect on Concentration of Nevirapine
or Concomitant Drug
Clinical Comment
Atazanavir/Ritonavir ↓ Atazanavir

↑ Nevirapine
Do not coadminister nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure.
Clarithromycin ↓ Clarithromycin

↑ 14-OH clarithromycin
Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.
Efavirenz ↓ Efavirenz There has been no determination of appropriate doses for the safe and effective use of this combination [see Warnings and Precautions (5.4) ].
Ethinyl estradiol and
Norethindrone
↓ Ethinyl estradiol

↓ Norethindrone
Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended.
Fluconazole ↑ Nevirapine Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration and patients should be monitored closely for nevirapine-associated adverse events.
Fosamprenavir ↓ Amprenavir

↑ Nevirapine
Coadministration of nevirapine and fosamprenavir without ritonavir is not recommended.
Fosamprenavir/Ritonavir ↓ Amprenavir

↑ Nevirapine
No dosing adjustments are required when nevirapine is coadministered with
700 mg/100 mg of fosamprenavir/ritonavir twice daily.
Indinavir ↓ Indinavir Appropriate doses for this combination are not established, but an increase in the dosage of indinavir may be required.
Ketoconazole ↓ Ketoconazole Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.
Lopinavir/Ritonavir ↓ Lopinavir A dose increase of lopinavir/ritonavir tablets to 500 mg/125 mg twice daily is recommended when used in combination with nevirapine.
A dose increase of lopinavir/ritonavir oral solution to 533 mg/133 mg twice daily with food is recommended in combination with nevirapine.

In children 6 months to 12 years of age receiving lopinavir/ritonavir solution, consideration should be given to increasing the dose of lopinavir/ritonavir to 13/3.25 mg/kg for those 7 kg to < 15 kg; 11/2.75 mg/kg for those 15 kg to 45 kg; up to a maximum dose of 533 mg/133 mg twice daily.

Refer to the lopinavir/ritonavir package insert for complete pediatric dosing instructions when lopinavir/ritonavir tablets are used in combination with nevirapine.
Methadone ↓ Methadone Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Nelfinavir ↓ Nelfinavir M8 Metabolite
↓ Nelfinavir Cmin
The appropriate dose for nelfinavir in combination with nevirapine, with respect to safety and efficacy, has not been established.
Rifabutin ↑ Rifabutin Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.
Rifampin ↓ Nevirapine Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Saquinavir/Ritonavir The interaction between nevirapine and saquinavir/ritonavir has not been evaluated The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
Potential Drug Interactions:
Drug Class Examples of Drugs
Antiarrhythmics Amiodarone, disopyramide, lidocaine Plasma concentrations may be decreased.
Anticonvulsants Carbamazepine, clonazepam, ethosuximide Plasma concentrations may be decreased.
Antifungals Itraconazole Plasma concentrations of some azole antifungals may be decreased. Nevirapine and itraconazole should not be administered concomitantly due to a potential decrease in itraconazole plasma concentrations.
Calcium channel blockers Diltiazem, nifedipine, verapamil Plasma concentrations may be decreased.
Cancer chemotherapy Cyclophosphamide Plasma concentrations may be decreased.
Ergot alkaloids Ergotamine Plasma concentrations may be decreased.
Immunosuppressants Cyclosporin, tacrolimus, sirolimus Plasma concentrations may be decreased.
Motility agents Cisapride Plasma concentrations may be decreased.
Opiate agonists Fentanyl Plasma concentrations may be decreased.
Antithrombotics Warfarin Plasma concentrations may be increased. Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.


Table name:
Interacting Drug Interaction
Theophylline Serious and fatal reactions. Avoid concomitant use. Monitor serum level ( 7)
Warfarin Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding ( 7)
Antidiabetic agents Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose ( 7)
Phenytoin Monitor phenytoin level ( 7)
Methotrexate Monitor for methotrexate toxicity ( 7)
Cyclosporine May increase serum creatinine. Monitor serum creatinine ( 7)
Multivalent cation-containing products including antacids, metal cations or didanosine Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin ( 7)


Table name:
Table 3Drugs that Can Increase the Risk of Bleeding
Drug  Class
Specific  Drugs
Anticoagulants 
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin 
Antiplatelet Agents 
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine 
Nonsteroidal Anti-Inflammatory Agents 
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac 
Serotonin Reuptake Inhibitors 
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone 


Table name:
Table 5. Established and Other Potentially Significant Drug Interactions
↓= Decreased (induces lamotrigine glucuronidation).
↑= Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
C oncomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine ↓levonorgestrel Decreased lamotrigine concentrations approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine and Carbamazepine epoxide ↓ lamotrigine ? carbamazepine epoxide Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels.
Lopinavir/ritonavir ↓ lamotrigine Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir ↓ lamotrigine Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine ? valproate Increased lamotrigine concentrations slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.


Table name: 0.6 mg (1 tablet) for 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Not to be repeated before 3 days.Prophylaxis of gout flares: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.

If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.Treatment of familial Mediterranean fever (FMF): Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).For patients who have been receiving REYATAZ/ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based on individual tolerability.Coadministration of REYATAZ/ritonavir in patients on bosentan: Discontinue bosentan at least 36 hours before starting REYATAZ/ritonavir. At least 10 days after starting REYATAZ/ritonavir, resume bosentan at 62.5 mg once daily or every other day based on individual tolerability.Use of REVATIO® (sildenafil) for the treatment of pulmonary hypertension (PAH) is contraindicated with REYATAZ [see Contraindications (4) ].

The following dose adjustments are recommended for the use of ADCIRCA® (tadalafil) with REYATAZ:

Coadministration of ADCIRCA® in patients on REYATAZ (with or without ritonavir):
For patients receiving REYATAZ (with or without ritonavir) for at least one week, start ADCIRCA® at 20 mg once daily. Increase to 40 mg once daily based on individual tolerability.

Coadministration of REYATAZ (with or without ritonavir) in patients on ADCIRCA®:
Avoid the use of ADCIRCA® when starting REYATAZ (with or without ritonavir). Stop ADCIRCA® at least 24 hours before starting REYATAZ (with or without ritonavir). At least one week after starting REYATAZ (with or without ritonavir), resume ADCIRCA® at 20 mg once daily. Increase to 40 mg once daily based on individual tolerability.
Table 13: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studiesa or Predicted Interactions (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated)
Concomitant Drug Class:
Specific Drugs
Effect on Concentration of Atazanavir or Concomitant Drug Clinical Comment
a For magnitude of interactions see Clinical Pharmacology, Tables 17 and 18 (12.3) .
b See Contraindications (4), Table 3 for orally administered midazolam.
c In combination with atazanavir 300 mg and ritonavir 100 mg once daily.
d In combination with atazanavir 400 mg once daily.
HIV Antiviral Agents
Nucleoside Reverse Transcriptase Inhibitors (NRTIs):
didanosine buffered formulations enteric-coated (EC) capsules
↓ atazanavir
↓ didanosine
Coadministration of REYATAZ with didanosine buffered tablets resulted in a marked decrease in atazanavir exposure. It is recommended that REYATAZ be given (with food) 2 h before or 1 h after didanosine buffered formulations. Simultaneous administration of didanosine EC and REYATAZ with food results in a decrease in didanosine exposure. Thus, REYATAZ and didanosine EC should be administered at different times.
Nucleotide Reverse Transcriptase Inhibitors: tenofovir disoproxil fumarate ↓ atazanavir
↑ tenofovir
Tenofovir may decrease the AUC and Cmin of atazanavir. When coadministered with tenofovir, it is recommended that REYATAZ 300 mg be given with ritonavir 100 mg and tenofovir 300 mg (all as a single daily dose with food). REYATAZ without ritonavir should not be coadministered with tenofovir. REYATAZ increases tenofovir concentrations. The mechanism of this interaction is unknown. Higher tenofovir concentrations could potentiate tenofovir-associated adverse events, including renal disorders. Patients receiving REYATAZ and tenofovir should be monitored for tenofovir-associated adverse events. For pregnant women taking REYATAZ with ritonavir and tenofovir, see Dosage and Administration (2.3) .
Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs): efavirenz ↓ atazanavir Efavirenz decreases atazanavir exposure.
In treatment-naive patients:
If REYATAZ is combined with efavirenz, REYATAZ 400 mg (two 200-mg capsules) with ritonavir 100 mg should be administered once daily all as a single dose with food, and efavirenz 600 mg should be administered once daily on an empty stomach, preferably at bedtime.
In treatment-experienced patients:
Do not coadminister REYATAZ with efavirenz in treatment-experienced patients due to decreased atazanavir exposure.
Non-nucleoside Reverse Transcriptase Inhibitors: nevirapine ↓ atazanavir
↑ nevirapine
Do not coadminister REYATAZ with nevirapine because: Nevirapine substantially decreases atazanavir exposure. Potential risk for nevirapine associated toxicity due to increased nevirapine exposures.
Protease Inhibitors: saquinavir (soft gelatin capsules) ↑ saquinavir Appropriate dosing recommendations for this combination, with or without ritonavir, with respect to efficacy and safety have not been established. In a clinical study, saquinavir 1200 mg coadministered with REYATAZ 400 mg and tenofovir 300 mg (all given once daily) plus nucleoside analogue reverse transcriptase inhibitors did not provide adequate efficacy [see Clinical Studies (14.2) ].
Protease Inhibitors: ritonavir ↑ atazanavir If REYATAZ is coadministered with ritonavir, it is recommended that REYATAZ 300 mg once daily be given with ritonavir 100 mg once daily with food. See the complete prescribing information for NORVIR® (ritonavir) for information on drug interactions with ritonavir.
Protease Inhibitors: others ↑ other protease inhibitor REYATAZ/ritonavir: Although not studied, the coadministration of REYATAZ/ritonavir and other protease inhibitors would be expected to increase exposure to the other protease inhibitor. Such coadministration is not recommended.
Other Agents
Antacids and buffered medications ↓ atazanavir Reduced plasma concentrations of atazanavir are expected if antacids, including buffered medications, are administered with REYATAZ. REYATAZ should be administered 2 hours before or 1 hour after these medications.
Antiarrhythmics: amiodarone, bepridil, lidocaine (systemic), quinidine ↑ amiodarone, bepridil, lidocaine (systemic), quinidine Coadministration with REYATAZ has the potential to produce serious and/or life-threatening adverse events and has not been studied. Caution is warranted and therapeutic concentration monitoring of these drugs is recommended if they are used concomitantly with REYATAZ (atazanavir sulfate).
Anticoagulants: warfarin ↑ warfarin Coadministration with REYATAZ has the potential to produce serious and/or life-threatening bleeding and has not been studied. It is recommended that INR (International Normalized Ratio) be monitored.
Antidepressants: tricyclic antidepressants ↑ tricyclic antidepressants Coadministration with REYATAZ has the potential to produce serious and/or life-threatening adverse events and has not been studied. Concentration monitoring of these drugs is recommended if they are used concomitantly with REYATAZ.
trazodone ↑ trazodone Concomitant use of trazodone and REYATAZ with or without ritonavir may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as REYATAZ, the combination should be used with caution and a lower dose of trazodone should be considered.
Antifungals: ketoconazole, itraconazole REYATAZ/ritonavir:
↑ ketoconazole
↑ itraconazole
Coadministration of ketoconazole has only been studied with REYATAZ without ritonavir (negligible increase in atazanavir AUC and Cmax). Due to the effect of ritonavir on ketoconazole, high doses of ketoconazole and itraconazole (>200 mg/day) should be used cautiously with REYATAZ/ritonavir.
Antifungals: voriconazole Effect is unknown Coadministration of voriconazole with REYATAZ, with or without ritonavir, has not been studied. Administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%. Voriconazole should not be administered to patients receiving REYATAZ/ritonavir, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Coadministration of voriconazole with REYATAZ (without ritonavir) may increase atazanavir concentrations; however, no data are available.
Antigout: colchicine ↑ colchicine REYATAZ should not be coadministered with colchicine to patients with renal or hepatic impairment.
Recommended dosage of colchicine when administered with REYATAZ:
Treatment of gout flares:
Antimycobacterials: rifabutin ↑ rifabutin A rifabutin dose reduction of up to 75% (eg, 150 mg every other day or 3 times per week) is recommended. Increased monitoring for rifabutin-associated adverse reactions including neutropenia is warranted.
Benzodiazepines: parenterally administered midazolamb ↑ midazolam Concomitant use of parenteral midazolam with REYATAZ may increase plasma concentrations of midazolam. Coadministration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Coadministration of oral midazolam with REYATAZ is CONTRAINDICATED.
Calcium channel blockers: diltiazem ↑ diltiazem and desacetyl-diltiazem Caution is warranted. A dose reduction of diltiazem by 50% should be considered. ECG monitoring is recommended. Coadministration of REYATAZ/ritonavir with diltiazem has not been studied.
eg, felodipine, nifedipine, nicardipine, and verapamil ↑ calcium channel blocker Caution is warranted. Dose titration of the calcium channel blocker should be considered. ECG monitoring is recommended.
Endothelin receptor antagonists: bosentan ↓ atazanavir
↑ bosentan
Plasma concentrations of atazanavir may be decreased when bosentan is administered with REYATAZ without ritonavir. Coadministration of bosentan and REYATAZ without ritonavir is not recommended.
Coadministration of bosentan in patients on REYATAZ/ritonavir:
HMG-CoA reductase inhibitors: atorvastatin, rosuvastatin ↑ atorvastatin
↑ rosuvastatin
Use the lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin or fluvastatin in combination with REYATAZ (with or without ritonavir). The risk of myopathy, including rhabdomyolysis, may be increased when HIV protease inhibitors, including REYATAZ, are used in combination with these drugs.
H2-Receptor antagonists ↓ atazanavir Plasma concentrations of atazanavir were substantially decreased when REYATAZ 400 mg once daily was administered simultaneously with famotidine 40 mg twice daily, which may result in loss of therapeutic effect and development of resistance.
    In treatment-naive patients:
REYATAZ 300 mg with ritonavir 100 mg once daily with food should be administered simultaneously with, and/or at least 10 hours after, a dose of the H2-receptor antagonist. An H2-receptor antagonist dose comparable to famotidine 20 mg once daily up to a dose comparable to famotidine 40 mg twice daily can be used with REYATAZ 300 mg with ritonavir 100 mg in treatment-naive patients.
                        OR
For patients unable to tolerate ritonavir, REYATAZ 400 mg once daily with food should be administered at least 2 hours before and at least 10 hours after a dose of the H2-receptor antagonist. No single dose of the H2-receptor antagonist should exceed a dose comparable to famotidine 20 mg, and the total daily dose should not exceed a dose comparable to famotidine 40 mg. However, REYATAZ should not be used without ritonavir in pregnant women.
    In treatment-experienced patients:
Whenever an H2-receptor antagonist is given to a patient receiving REYATAZ with ritonavir, the H2-receptor antagonist dose should not exceed a dose comparable to famotidine 20 mg twice daily, and the REYATAZ and ritonavir doses should be administered simultaneously with, and/or at least 10 hours after, the dose of the H2-receptor antagonist. REYATAZ 300 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with an H2-receptor antagonist. For pregnant women taking REYATAZ with ritonavir and an H2-receptor antagonist, see Dosage and Administration (2.3) . REYATAZ 400 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with both tenofovir and an H2-receptor antagonist. For pregnant women taking REYATAZ with ritonavir and both tenofovir and an H2-receptor antagonist, see Dosage and Administration (2.3) .
Hormonal contraceptives: ethinyl estradiol and norgestimate or norethindrone ↓ ethinyl estradiol
↑ norgestimatec
↑ ethinyl estradiol
↑ norethindroned
Use with caution if coadministration of REYATAZ or REYATAZ/ritonavir with oral contraceptives is considered. If an oral contraceptive is administered with REYATAZ plus ritonavir, it is recommended that the oral contraceptive contain at least 35 mcg of ethinyl estradiol. If REYATAZ is administered without ritonavir, the oral contraceptive should contain no more than 30 mcg of ethinyl estradiol.
     Potential safety risks include substantial increases in progesterone exposure. The long-term effects of increases in concentration of the progestational agent are unknown and could increase the risk of insulin resistance, dyslipidemia, and acne.
     Coadministration of REYATAZ or REYATAZ/ritonavir with other hormonal contraceptives (eg, contraceptive patch, contraceptive vaginal ring, or injectable contraceptives) or oral contraceptives containing progestogens other than norethindrone or norgestimate, or less than 25 mcg of ethinyl estradiol, has not been studied; therefore, alternative methods of contraception are recommended.
Immunosuppressants: cyclosporin, sirolimus, tacrolimus ↑ immunosuppressants Therapeutic concentration monitoring is recommended for immunosuppressant agents when coadministered with REYATAZ (atazanavir sulfate).
Inhaled beta agonist: salmeterol ↑ salmeterol Coadministration of salmeterol with REYATAZ is not recommended. Concomitant use of salmeterol and REYATAZ may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.
Inhaled/nasal steroid: fluticasone REYATAZ
↑ fluticasone
Concomitant use of fluticasone propionate and REYATAZ (without ritonavir) may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use.
  REYATAZ/ritonavir
↑ fluticasone
Concomitant use of fluticasone propionate and REYATAZ/ritonavir may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects, including Cushing’s syndrome and adrenal suppression, have been reported during postmarketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Coadministration of fluticasone propionate and REYATAZ/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects [see Warnings and Precautions (5.1) ].
Macrolide antibiotics: clarithromycin ↑ clarithromycin
↓ 14-OH clarithromycin
↑ atazanavir
Increased concentrations of clarithromycin may cause QTc prolongations; therefore, a dose reduction of clarithromycin by 50% should be considered when it is coadministered with REYATAZ. In addition, concentrations of the active metabolite 14-OH clarithromycin are significantly reduced; consider alternative therapy for indications other than infections due to Mycobacterium avium complex. Coadministration of REYATAZ/ritonavir with clarithromycin has not been studied.
Opioids: Buprenorphine ↑ buprenorphine
↑ norbuprenorphine
Coadministration of buprenorphine and REYATAZ with or without ritonavir increases the plasma concentration of buprenorphine and norbuprenorphine. Coadministration of REYATAZ plus ritonavir with buprenorphine warrants clinical monitoring for sedation and cognitive effects. A dose reduction of buprenorphine may be considered. Coadministration of buprenorphine and REYATAZ with ritonavir is not expected to decrease atazanavir plasma concentrations. Coadministration of buprenorphine and REYATAZ without ritonavir may decrease atazanavir plasma concentrations. REYATAZ without ritonavir should not be coadministered with buprenorphine.
PDE5 inhibitors: sildenafil, tadalafil, vardenafil ↑ sildenafil
↑ tadalafil
↑ vardenafil
Coadministration with REYATAZ has not been studied but may result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism.

Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH):
  Use of PDE5 inhibitors for erectile dysfunction:         Use VIAGRA® (sildenafil) with caution at reduced doses of 25 mg every 48 hours with increased monitoring for adverse events.
        Use CIALIS® (tadalafil) with caution at reduced doses of 10 mg every 72 hours with increased monitoring for adverse events.
        REYATAZ/ritonavir: Use LEVITRA® (vardenafil) with caution at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring for adverse events.
        REYATAZ: Use LEVITRA® (vardenafil) with caution at reduced doses of no more than 2.5 mg every 24 hours with increased monitoring for adverse events.
Proton-pump inhibitors: omeprazole ↓ atazanavir Plasma concentrations of atazanavir were substantially decreased when REYATAZ 400 mg or REYATAZ 300 mg/ritonavir 100 mg once daily was administered with omeprazole 40 mg once daily, which may result in loss of therapeutic effect and development of resistance.
    In treatment-naive patients:
The proton-pump inhibitor dose should not exceed a dose comparable to omeprazole 20 mg and must be taken approximately 12 hours prior to the REYATAZ 300 mg with ritonavir 100 mg dose.
    In treatment-experienced patients:
Proton-pump inhibitors should not be used in treatment-experienced patients receiving REYATAZ.


Table name:
Table 8: Drugs That are Affected by and Affecting ciprofloxacin
Drugs That are Affected by ciprofloxacin
Drug(s) Recommendation
Comments
Tizanidine
Contraindicated
Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)]
Theophylline
Avoid Use
 (Plasma Exposure Likely to be Increased and Prolonged)


Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions (5.9)].
Drugs Known to Prolong QT Interval
Avoid Use
Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.11) and Use in Specific Populations (8.5)].
Oral antidiabetic drugs
Use with caution
                       Glucose-lowering effect potentiated


Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs [see Adverse Reactions (6.1)].
Phenytoin
Use with caution
 Altered serum levels of phenytoin (increased and decreased)


To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin with phenytoin.
Cyclosporine
Use with caution
 (transient elevations in serum creatinine)


Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs
Use with caution
 (Increase in anticoagulant effect)


The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate
Use with caution
Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels


Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole
Use with caution
Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin [see Warnings and Precautions (5.15)].
Clozapine
Use with caution
Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs
Use with caution
Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil
Use with caution
 Two-fold increase in exposure


Monitor for sildenafil toxicity [see Clinical Pharmacology (12.3)].
Duloxetine
Avoid Use
 Five-fold increase in duloxetine exposure


If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives
Use with caution
 Reduced clearance resulting in elevated levels and prolongation of serum half-life


Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of ciprofloxacin
Probenecid
Use with caution
 (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)


Potentiation of ciprofloxacin toxicity may occur.


Table name:
Table 6: Selected Drug Interactions
Concomitant Drug Class: Drug Name Effect on Concentration of Raltegravir Clinical Comment
HIV-1-Antiviral Agents
atazanavir Atazanavir, a strong inhibitor of UGT1A1, increases plasma concentrations of raltegravir. However, since concomitant use of ISENTRESS with atazanavir/ritonavir did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended.
atazanavir/ritonavir Atazanavir/ritonavir increases plasma concentrations of raltegravir. However, since concomitant use of ISENTRESS with atazanavir/ritonavir did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended.
efavirenz Efavirenz reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.
etravirine Etravirine reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.
tipranavir/ritonavir Tipranavir/ritonavir reduces plasma concentrations of raltegravir. However, since comparable efficacy was observed for this combination relative to other ISENTRESS-containing regimens in Phase 3 studies 018 and 019, no dose adjustment is recommended.
Other Agents
omeprazole Coadministration of medicinal products that increase gastric pH (e.g., omeprazole) may increase raltegravir levels based on increased raltegravir solubility at higher pH. However, since concomitant use of ISENTRESS with proton pump inhibitors and H2 blockers did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended.
rifampin Rifampin, a strong inducer of UGT1A1, reduces plasma concentrations of raltegravir. The recommended dosage of ISENTRESS is 800 mg twice daily during coadministration with rifampin.


Table name:
Table 2. Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T4 and T3 serum transport - but FT4 concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors
(SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Interacting Agents Prescribing Recommendations
Strong CYP3A4 Inhibitors, (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol Contraindicated with ezetimibe and simvastatin tablets
Verapamil, diltiazem, dronedarone Do not exceed ezetimibe and simvastatin tablets, 10 mg/10 mg daily
Amiodarone, amlodipine, ranolazine Do not exceed ezetimibe and simvastatin tablets, 10 mg/20 mg daily
Lomitapide For patients with HoFH, do not exceed 10 mg/20 mg ezetimibe and simvastatin tabletsFor patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 10 mg/40 mg ezetimibe and simvastatin tablets when taking lomitapide.
Grapefruit juice Avoid grapefruit juice


Table name:
Figure 1: Effect of interacting drugs on the pharmacokinetics of venlafaxine and active metabolite O-desmethylvenlafaxine (ODV).


Table name:
  Interacting Drug  Interaction
 Multivalent cation-containing products including antacids, metal cations or didanosine  Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
 Warfarin  Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
 Antidiabetic agents  Carefully monitor blood glucose (5.11, 7.3)


Table name:
 Factors  Dosage Adjustments for Aripiprazole
 Known CYP2D6 Poor Metabolizers  Administer half of usual dose
 Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors  Administer a quarter of usual dose
 Strong CYP2D6 or CYP3A4 inhibitors  Administer half of usual dose
 Strong CYP2D6 and CYP3A4 inhibitors  Administer a quarter of usual dose
 Strong CYP3A4 inducers  Double usual dose over 1 to 2 weeks


Table name:
DRUG DESCRIPTION OF INTERACTION
Heparin Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients.
Pyrazinamide Inhibits pyrazinamide-induced hyperuricemia.
Uricosuric Agents Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited.


Table name:
 Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
 Interacting Agents  Prescribing Recommendations
 Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)  Avoid atorvastatin
 HIV protease inhibitor (lopinavir plus ritonavir)  Use with caution and lowest dose necessary
 Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)  Do not exceed 20 mg atorvastatin daily
 HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
 Do not exceed 40 mg atorvastatin daily


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may
result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-
   containing radiographic
   contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which
may result in hyperthyroidism
Amiodarone
Iodide (including iodine-
containing Radiographic
contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase Drugs that may decrease
serum TBG concentration serum TBG concentration
Clofibrate Androgens / Anabolic Steroids
Estrogen-containing oral Asparaginase
   contraceptives Glucocorticoids
Estrogens (oral) Slow-Release Nicotinic Acid
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal
Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake
Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
NITROPRUSSIDE
Para-aminosalicylate sodium
Perphenazine
Resorcinol
 (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Strong CYP3A4 Inhibitors
Clinical Impact: Concomitant use of REXULTI with strong CYP3A4 inhibitors increased the exposure of brexpiprazole compared to the use of REXULTI alone [see Clinical Pharmacology (12.3)]
Intervention: With concomitant use of REXULTI with a strong CYP3A4 inhibitor, reduce the REXULTI dosage [see Dosage and Administration (2.5)]
Examples: itraconazole, clarithromycin, ketoconazole
Strong CYP2D6 Inhibitors*
Clinical Impact: Concomitant use of REXULTI with strong CYP2D6 inhibitors increased the exposure of brexpiprazole compared to the use of REXULTI alone [see Clinical Pharmacology (12.3)]
Intervention: With concomitant use of REXULTI with a strong CYP2D6 inhibitor, reduce the REXULTI dosage [see Dosage and Administration (2.5)]
Examples: paroxetine, fluoxetine, quinidine
Both CYP3A4 Inhibitors and CYP2D6 Inhibitors
Clinical Impact: Concomitant use of REXULTI with 1) a strong CYP3A4 inhibitor and a strong CYP2D6 inhibitor; or 2) a moderate CYP3A4 inhibitor and a strong CYP2D6 inhibitor; or 3) a strong CYP3A4 inhibitor and a moderate CYP2D6 inhibitor; or 4) a moderate CYP3A4 inhibitor and a moderate CYP2D6 inhibitor, increased the exposure of brexpiprazole compared to the use of REXULTI alone [see Clinical Pharmacology (12.3)]
Intervention: With concomitant use of REXULTI with 1) a strong CYP3A4 inhibitor and a strong CYP2D6 inhibitor; or 2) a moderate CYP3A4 inhibitor and a strong CYP2D6 inhibitor; or 3) a strong CYP3A4 inhibitor and a moderate CYP2D6 inhibitor; or 4) a moderate CYP3A4 inhibitor and a moderate CYP2D6 inhibitor, decrease the REXULTI dosage [see Dosage and Administration (2.5)]
Examples: 1) itraconazole + quinidine 2) fluconazole + paroxetine 3) itraconazole + duloxetine 4) fluconazole + duloxetine
Strong CYP3A4 Inducers
Clinical Impact: Concomitant use of REXULTI and a strong CYP3A4 inducer decreased the exposure of brexpiprazole compared to the use of REXULTI alone [see Clinical Pharmacology (12.3)]
Intervention: With concomitant use of REXULTI with a strong CYP3A4 inducer, increase the REXULTI dosage [see Dosage and Administration (2.5)]
Examples: rifampin, St. John’s wort


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T 4 and T 3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin/Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens/Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non-Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT 4 . Continued administration results in a decrease in serum T 4 and normal FT 4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T 4 and T 3 to TBG and transthyretin. An initial increase in serum FT 4 is followed by return of FT 4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T 4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T 4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ³ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T 4 to T 3, leading to decreased T 3 levels. However, serum T 4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T 3 and T 4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T 3 concentrations by 30% with minimal change in serum T 4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T 3 and T 4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias
and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123 I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 7: Effect of Voriconazole on Pharmacokinetics of Other Drugs [see Clinical Pharmacology (12.3)]
Drug/Drug Class
(Mechanism of Interaction by Voriconazole)
Drug Plasma Exposure (Cmax and AUCτ) Recommendations for Drug Dosage Adjustment/Comments
SirolimusResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects
(CYP3A4 Inhibition)
Significantly Increased Contraindicated
Rifabutin
(CYP3A4 Inhibition)
Significantly Increased Contraindicated
Efavirenz (400 mg q24h)Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects
(CYP3A4 Inhibition)
Significantly Increased Contraindicated
Efavirenz (300 mg q24h)
(CYP3A4 Inhibition)
Slight Increase in AUCτ When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)(CYP3A4 Inhibition)


Low-dose Ritonavir (100 mg q12h)
No Significant Effect of Voriconazole on Ritonavir Cmax or AUCτ


Slight Decrease in Ritonavir Cmax and AUCτ
Contraindicated because of significant reduction of voriconazole Cmax and AUCτ

Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole Cmax and AUCτ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine
(CYP3A4 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids
(CYP450 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Contraindicated
Cyclosporine
(CYP3A4 Inhibition)
AUCτ Significantly Increased; No Significant Effect on Cmax When initiating therapy with voriconazole in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When voriconazole is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
MethadoneResults based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for 4 days voriconazole to subjects receiving a methadone maintenance dose (30–100 mg q24h) (CYP3A4 Inhibition) Increased Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl (CYP3A4 Inhibition)
Increased Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7)]
Alfentanil (CYP3A4 Inhibition) Significantly Increased Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with voriconazole. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [see Drug Interactions (7)].
Oxycodone (CYP3A4 Inhibition) Significantly Increased Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7)].
NSAIDsNon-Steroidal Anti-Inflammatory Drug including. ibuprofen and diclofenac
(CYP2C9 Inhibition)
Increased Frequent monitoring for adverse events
and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed [see Drug Interactions (7)].
Tacrolimus
(CYP3A4 Inhibition)
Significantly Increased When initiating therapy with voriconazole in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazole is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin
(CYP2C9 Inhibition)
Significantly Increased Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition) Increased Monitoring for adverse events related to oral contraceptives is recommended during coadministration.
Warfarin
(CYP2C9 Inhibition)
Prothrombin Time Significantly Increased Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed.
Omeprazole
(CYP2C19/3A4 Inhibition)
Significantly Increased When initiating therapy with voriconazole in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors
(CYP3A4 Inhibition)
In Vivo Studies Showed No Significant Effects on Indinavir Exposure

In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism
(Increased Plasma Exposure)
No dosage adjustment for indinavir when coadministered with voriconazole

Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors
(CYP3A4 Inhibition)
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs
(Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity related to NNRTI
Benzodiazepines
(CYP3A4 Inhibition)
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism
(Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.
HMG-CoA Reductase Inhibitors (Statins)
(CYP3A4 Inhibition)
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism
(Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers
(CYP3A4 Inhibition)
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism
(Increased Plasma Exposure)
Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics
(CYP2C9 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids
(CYP3A4 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed.
Everolimus
(CYP3A4 Inhibition)
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Concomitant administration of voriconazole and everolimus is not recommended.


Table name:
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitors (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.11, 7.3)


Table name:
Table 3 Clinically Significant Drug Interactions with Meloxicam
Drugs  that  Interfere  with  Hemostasis
Clinical  Impact :
Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.
Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. 
Intervention :
Monitor patients with concomitant use of meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ see  WARNINGS  AND  PRECAUTIONS  ( 5 . 11 )].
Aspirin
Clinical  Impact :
Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ see  WARNINGS  AND  PRECAUTIONS  ( 5 . 2 )].
Intervention :
Concomitant use of meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see  WARNINGS  AND  PRECAUTIONS  ( 5 . 11 )]. 

Meloxicam is not a substitute for low dose aspirin for cardiovascular protection.
ACE  Inhibitors Angiotensin  Receptor  Blockers or  Beta - Blockers
Clinical  Impact :
NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).
In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention :
During concomitant use of meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.
During concomitant use of meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ see  WARNINGS  AND  PRECAUTIONS  ( 5 . 6 )]. 
When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical  Impact :
Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam.
Intervention :
During concomitant use of meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ see  WARNINGS  AND  PRECAUTIONS  ( 5 . 6 )].
Lithium
Clinical  Impact :
NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [ see  CLINICAL  PHARMACOLOGY  ( 12 . 3 )].
Intervention :
During concomitant use of meloxicam and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical  Impact :
Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention :
During concomitant use of meloxicam and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical  Impact :
Concomitant use of meloxicam and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention :
During concomitant use of meloxicam and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs  and  Salicylates
Clinical  Impact :
Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ see  WARNINGS  AND  PRECAUTIONS  ( 5 . 2 )].
Intervention :
The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical  Impact :
Concomitant use of meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention :
During concomitant use of meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.
Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
 Interacting Agents  Prescribing Recommendations
 Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)  Avoid atorvastatin
 HIV protease inhibitor (lopinavir plus ritonavir)  Use with caution and lowest dose necessary
 Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)  Do not exceed 20 mg atorvastatin daily
 HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)  Do not exceed 40 mg atorvastatin daily


Table name:
AED Coadministered AED Concentration Topiramate Concentration
Phenytoin
NC or 25% increase Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
48% decrease


Carbamazepine (CBZ)
NC
40% decrease
CBZ epoxide Is not administered but is an active metabolite of carbamazepine.
NC
NE
Valproic acid
11% decrease
14% decrease
Phenobarbital
NC
NE
Primidone
NC
NE
Lamotrigine
NC at TPM doses up to 400 mg/day
13% decrease


Table name:
edema
hereditary coumarin resistance
hyperlipemia
hypothyroidism
nephrotic syndrome


Table name:
Table 4 Other Potentially Significant Drug Interactions
Concomitant Drug Class or Food Noted or anticipated Outcome Clinical Comment
HMG-Co A Reductase Inhibitors:
atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin
Pharmacokinetic and/or pharmacodynamic interaction: the addition of one drug to a stable long-term regimen of the other has resulted in myopathy and rhabdomyolysis (including a fatality) Weigh the potential benefits and risks and carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during initial therapy; monitoring CPK (creatine phosphokinase) will not necessarily prevent the occurrence of severe myopathy.
Other Lipid Lowering Drugs:
fibrates, gemfibrozil
Digitalis Glycosides:
digoxin
P-gp substrate; rhabdomyolysis has been reported


Table name:
Table 4. Mean (95% C.I.) maximal change in baseline in systolic blood pressure (mmHg) following vardenafil 10 and 20 mg in healthy volunteers on daily alpha-blocker therapy
Dosing of Vardenafil and Alpha-Blocker Separated by 6 Hours Simultaneous dosing of Vardenafil and Alpha-Blocker
Alpha-Blocker Vardenafil
10 mg
Placebo-Subtracted
Vardenafil
20 mg
Placebo-Subtracted
Vardenafil
10 mg
Placebo-Subtracted
Vardenafil
20 mg
Placebo-Subtracted
Terazosin
10 mg daily
Standing SBP -7 (-10, -3) -11 (-14, -7) -23 (-31, 16) Due to the sample size, confidence intervals may not be an accurate measure for these data. These values represent the range for the difference. -14 (-33, 11)
Supine SBP -5 (-8, -2) -7 (-11, -4) -7 (-25, 19) -7 (-31, 22)
Tamsulosin
0.4 mg daily
Standing SBP -4 (-8, -1) -8 (-11, -4) -8 (-14, -2) -8 (-14, -1)
Supine SBP -4 (-8, 0) -7 (-11, -3) -5 (-9, -2) -3 (-7, 0)


Table name:
Table 8: Clinically Significant Drug Interactions with Clarithromycin
Drugs That Are Affected By Clarithromycin
Drug(s) with Pharmacokinetics Affected by Clarithromycin
Recommendation
Comments
Antiarrhythmics:
 
Disopyramide
Quinidine
Dofetilide
Amiodarone
Sotalol
Procainamide
 
 
 
 
Digoxin
 
 
Not Recommended
 
 
 
 
 
 
 
 
Use With Caution
 
 
Disopyramide, Quinidine: There have been postmarketing reports of torsades de pointes occurring with concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QTc prolongation during coadministration of clarithromycin with these drugs [see Warnings and Precautions (5.3)] .
 
Serum concentrations of these medications should also be monitored. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with disopyramide and quinidine.
 
There have been postmarketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide. Therefore, blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide.
 
Digoxin: Digoxin is a substrate for P-glycoprotein (Pgp) and clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are co-administered, inhibition of Pgp by clarithromycin may lead to increased exposure of digoxin. Elevated digoxin serum concentrations in patients receiving clarithromycin and digoxin concomitantly have been reported in postmarketing surveillance. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Monitoring of serum digoxin concentrations should be considered, especially for patients with digoxin concentrations in the upper therapeutic range.
Oral Anticoagulants:
 
Warfarin
 
 
Use With Caution
 
 
Oral anticoagulants: Spontaneous reports in the postmarketing period suggest that concomitant administration of clarithromycin and oral anticoagulants may potentiate the effects of the oral anticoagulants. Prothrombin times should be carefully monitored while patients are receiving clarithromycin and oral anticoagulants simultaneously [see Warnings and Precautions (5.4)] .
Antiepileptics:
 
Carbamazepine
 
 
Use With Caution
 
 
Carbamazepine: Concomitant administration of single doses of clarithromycin and carbamazepine has been shown to result in increased plasma concentrations of carbamazepine. Blood level monitoring of carbamazepine may be considered. Increased serum concentrations of carbamazepine were observed in clinical trials with clarithromycin. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with carbamazepine.
Antifungals:
 
Itraconazole
 
 
 

Fluconazole
 
 
Use With Caution
 
 
 

No Dose Adjustment
 
 
Itraconazole: Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when administered concomitantly (see also Itraconazole under “Drugs That Affect Clarithromycin” in the table below). Clarithromycin may increase the plasma concentrations of itraconazole. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions.
 
Fluconazole:  [see Pharmacokinetics (12.3)]
 

Anti-Gout Agents:
 
Colchicine (in patients with renal or hepatic impairment)
 
Colchicine (in patients with normal renal and hepatic function)
 
 
Contraindicated
 
 
Use With Caution
 
 
Colchicine: Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. The dose of colchicine should be reduced when co-administered with clarithromycin in patients with normal renal and hepatic function [see  Contraindications (4.4) and Warnings and Precautions (5.4)] .
Antipsychotics:
 
Pimozide
 
Quetiapine
 
 
Contraindicated
 
 
Pimozide:  [See Contraindications (4.2)]

Quetiapine: Quetiapine is a substrate for CYP3A4, which is inhibited by clarithromycin. Co-administration with clarithromycin could result in increased quetiapine exposure and possible quetiapine related toxicities. There have been postmarketing reports of somnolence, orthostatic hypotension, altered state of consciousness, neuroleptic malignant syndrome, and QT prolongation during concomitant administration. Refer to quetiapine prescribing information for recommendations on dose reduction if co-administered with CYP3A4 inhibitors such as clarithromycin.
Antispasmodics:
 
Tolterodine (patients deficient in CYP2D6 activity)
 
 
Use With Caution
 
 
Tolterodine: The primary route of metabolism for tolterodine is via. CYP2D6. However, in a subset of the population devoid of CYP2D6, the identified pathway of metabolism is via. CYP3A. In this population subset, inhibition of CYP3A results in significantly higher serum concentrations of tolterodine. Tolterodine 1 mg twice daily is recommended in patients deficient in CYP2D6 activity (poor metabolizers) when co-administered with clarithromycin.
Antivirals:
 
Atazanavir
 

Saquinavir (in patients with decreased renal function)
 
Ritonavir
Etravirine
 
Maraviroc
 

Boceprevir (in patients with normal renal function)
 
Didanosine
 
Zidovudine


 
 
Use With Caution
 
 
 
 
 
 
 
 
 
 

No Dose Adjustment
 
 
Atazanavir: Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction (see Atazanavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)] .
 
Saquinavir: Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A and there is evidence of a bi-directional drug interaction (see Saquinavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)] .
 
Ritonavir, Etravirine: (see Ritonavir and Etravirine under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)] .
 

Maraviroc
: Clarithromycin may result in increases in maraviroc exposures by inhibition of CYP3A metabolism. See Selzentry ® prescribing information for dose recommendation when given with strong CYP3A inhibitors such as clarithromycin.
 
Boceprevir: Both clarithromycin and boceprevir are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when co-administered. No dose adjustments are necessary for patients with normal renal function (see Victrelis ® prescribing information).
 


Zidovudine:
Simultaneous oral administration of clarithromycin immediate-release tablets and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine concentrations. Administration of clarithromycin and zidovudine should be separated by at least two hours [see Pharmacokinetics (12.3)] .
Calcium Channel Blockers:
 
Verapamil
 

Amlodipine
Diltiazem
 
Nifedipine
 
 
Use With Caution
 
 
Verapamil: Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent verapamil, [see Warnings and Precautions (5.4)] .
 
Amlodipine, Diltiazem: [See Warnings and Precautions (5.4)]

 
Nifedipine: Nifedipine is a substrate for CYP3A. Clarithromycin and other macrolides are known to inhibit CYP3A. There is potential of CYP3A-mediated interaction between nifedipine and clarithromycin. Hypotension and peripheral edema were observed when clarithromycin was taken concomitantly with nifedipine [see Warnings and Precautions (5.4)] .
Ergot Alkaloids:
 
Ergotamine
Dihydroergotamine
 
 
Contraindicated
 
 
Ergotamine, Dihydroergotamine: Postmarketing reports indicate that coadministration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system [see Contraindications (4.6)].
Gastroprokinetic  Agents:
 
Cisapride
 
 
Contraindicated
 
 
Cisapride: [See Contraindications (4.2)]
HMG-CoA Reductase Inhibitors:
 
Lovastatin
Simvastatin
 
Atorvastatin
Pravastatin
 
Fluvastatin

 
 
Contraindicated
 
 
Use With Caution
 
No Dose Adjustment
 
 
Lovastatin, Simvastatin, Atorvastatin, Pravastatin, Fluvastatin:  [See  Contraindications (4.5) and Warnings and Precautions (5.4)]
Hypoglycemic Agents:
 
Nateglinide
Pioglitazone
Repaglinide
Rosiglitazone
 
Insulin

 
 
Use With Caution
 
 
Nateglinide, Pioglitazone, Repaglinide, Rosiglitazone: [See Warnings and Precautions (5.4) and Adverse Reactions (6.2)]
 



Insulin: [See  Warnings and Precautions (5.4) and Adverse Reactions (6.2)]
Immunosuppressants:
 
Cyclosporine
 
Tacrolimus
 
 
Use With Caution
 
 
Cyclosporine: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with cyclosporine.
 
Tacrolimus: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with tacrolimus.
Phosphodiesterase inhibitors:
 
Sildenafil
Tadalafil
Vardenafil
 
 
 
Use With Caution
 
 
 
Sildenafil, Tadalafil, Vardenafil: Each of these phosphodiesterase inhibitors is primarily metabolized by CYP3A, and CYP3A will be inhibited by concomitant administration of clarithromycin. Co-administration of clarithromycin with sildenafil, tadalafil, or vardenafil will result in increased exposure of these phosphodiesterase inhibitors. Co-administration of these phosphodiesterase inhibitors with clarithromycin is not recommended. Increased systemic exposure of these drugs may occur with clarithromycin; reduction of dosage for phosphodiesterase inhibitors should be considered (see their respective prescribing information).
Proton Pump Inhibitors:
 
Omeprazole
 
 
No Dose Adjustment
 
 
Omeprazole: The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when coadministered with clarithromycin as a result of increased omeprazole exposures [see Pharmacokinetics (12.3)] (see also Omeprazole under “Drugs That Affect Clarithromycin” in the table below).
Xanthine Derivatives:
 
Theophylline
 
 
Use With Caution
 
 
Theophylline: Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serum theophylline concentrations [see Pharmacokinetics (12.3)] . Monitoring of serum theophylline concentrations should be considered for patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range.
Triazolobenzodiazepines and Other Related Benzodiazepines:
 
Midazolam
 
 
Alprazolam
Triazolam
 
 
 
 
 
Temazepam
Nitrazepam
Lorazepam
 
 
 
Use With Caution
 
 
 
 
 
 
 
 
 
No Dose Adjustment
 
 
 
Midazolam: When oral midazolam is co-administered with clarithromycin, dose adjustments may be necessary and possible prolongation and intensity of effect should be anticipated [see  Warnings and Precautions (5.4) and Pharmacokinetics (12.3)] .
 
Triazolam, Alprazolam: Caution and appropriate dose adjustments should be considered when triazolam or alprazolam is co-administered with clarithromycin. There have been postmarketing reports of drug interactions and central nervous system (CNS) effects (e.g., somnolence and confusion) with the concomitant use of clarithromycin and triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested.
 
In postmarketing experience, erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines.
 
Temazepam, Nitrazepam, Lorazepam: For benzodiazepines which are not metabolized by CYP3A (e.g., temazepam, nitrazepam, lorazepam), a clinically important interaction with clarithromycin is unlikely.
Cytochrome P450 Inducers:
 
Rifabutin
 
 
Use With Caution
 
 
Rifabutin: Concomitant administration of rifabutin and clarithromycin resulted in an increase in rifabutin, and decrease in clarithromycin serum levels together with an increased risk of uveitis (see Rifabutin under “Drugs That Affect Clarithromycin” in the table below).
Other Drugs
Metabolized by CYP3A:
 
Alfentanil
Bromocriptine
Cilostazol
Methylprednisole Vinblastine
Phenobarbital
St. John’s Wort
 
 
 
Use With Caution
 
 
 
There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with alfentanil, methylprednisolone, cilostazol, bromocriptine, vinblastine, phenobarbital, and St. John’s Wort.
Other Drugs Metabolized by CYP450 Isoforms Other than CYP3A:
 
Hexobarbital
Phenytoin
Valproate
 
 
 
 
Use With Caution
 
 
 
 
There have been postmarketing reports of interactions of clarithromycin with drugs not thought to be metabolized by CYP3A, including hexobarbital, phenytoin, and valproate.


                                                                                                                                       Drugs that Affect Clarithromycin
Drug(s) that Affect the Pharmacokinetics of Clarithromycin

Recommendation

                                                                                     Comments
Antifungals:
 
Itraconazole
 
 
Use With Caution
 
 
Itraconazole: Itraconazole may increase the plasma concentrations of clarithromycin. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions (see also Itraconazole under “Drugs That Are Affected By Clarithromycin” in the table above).
Antivirals:
 
Atazanavir
 
 
 
 
 
 
Ritonavir (in patients with decreased renal function)
 
 
Saquinavir (in patients with decreased renal function)
 
Etravirine
 
 
 
 
Saquinavir (in patients with normal renal function) Ritonavir (in patients with normal renal function)
 
 
Use With Caution
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
No Dose Adjustment
 
 
Atazanavir: When clarithromycin is co-administered with atazanavir, the dose of clarithromycin should be decreased by 50% [see Clinical Pharmacology (12.3)] .
 
Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with atazanavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium complex. Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.
 
Ritonavir: Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with ritonavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium [see Pharmacokinetics (12.3)] .
 
Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.
 
Saquinavir: When saquinavir is co-administered with ritonavir, consideration should be given to the potential effects of ritonavir on clarithromycin (refer to ritonavir above) [see Pharmacokinetics (12.3)] .
 
Etravirine: Clarithromycin exposure was decreased by etravirine; however, concentrations of the active metabolite, 14-OH-clarithromycin, were increased. Because 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered; therefore alternatives to clarithromycin should be considered for the treatment of MAC.
Proton Pump Inhibitors:
 
Omeprazole
 
 
Use With Caution
 
 
Omeprazole: Clarithromycin concentrations in the gastric tissue and mucus were also increased by concomitant administration of omeprazole [see Pharmacokinetics (12.3)] .
Miscellaneous Cytochrome P450 Inducers:
 
Efavirenz
Nevirapine
Rifampicin
Rifabutin
Rifapentine
 
 
 
Use With Caution
 
 
 
Inducers of CYP3A enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine will increase the metabolism of clarithromycin, thus decreasing plasma concentrations of clarithromycin, while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. Alternative antibacterial treatment should be considered when treating patients receiving inducers of CYP3A. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with rifabutin (see Rifabutin under “Drugs That Are Affected By Clarithromycin” in the table above).


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
  Concomitant Drug   Effect on Concentration of Lamotrigine or Concomitant Drug   Clinical Comment
  Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel   ↓ lamotrigine   Decreased lamotrigine levels approximately 50%.
     ↓ levonorgestrel   Decrease in levonorgestrel component by 19%.
  Carbamazepine (CBZ) and CBZ epoxide   ↓ lamotrigine   Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
     ? CBZ epoxide   May increase CBZ epoxide levels
  Phenobarbital/Primidone   ↓ lamotrigine   Decreased lamotrigine concentration approximately 40%.
  Phenytoin (PHT)   ↓ lamotrigine   Decreased lamotrigine concentration approximately 40%.
  Rifampin   ↓ lamotrigine   Decreased lamotrigine AUC approximately 40%.
  Valproate   ↑ lamotrigine   Increased lamotrigine concentrations slightly more than 2-fold.
     ? valproate   Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name: Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology (12.3)]. Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see Clinical Pharmacology (12.3)]. There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole.
Table 3: Clinically Relevant Interactions Affecting Drugs Co-Administered with Omeprazole and Interaction with Diagnostics
Antiretrovirals
Clinical Impact:
The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known.
Intervention:
Rilpivirine-containing products: Concomitant use with omeprazole is contraindicated [see Contraindications (4)].
 
Atazanavir: Avoid concomitant use with omeprazole. See prescribing information for atazanavir for dosing information.
 
Nelfinavir: Avoid concomitant use with omeprazole. See prescribing information for nelfinavir.
 
Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities.
 
Other antiretrovirals: See prescribing information for specific antiretroviral drugs.
Warfarin
Clinical Impact:
Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
Intervention:
Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range.
Methotrexate
Clinical Impact:
Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions (5.11)].
Intervention:
A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate.
CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam)
Clopidogrel
Clinical Impact:
Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology (12.3)].
There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel.
Intervention:
Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy [see Warnings and Precautions (5.6)].
Citalopram
Clinical Impact:
Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology (12.3)].
Intervention:
Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.
Cilostazol
Clinical Impact:
Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology (12.3)].
Intervention:
Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.
Phenytoin
Clinical Impact:
Potential for increased exposure of phenytoin.
Intervention:
Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin.
Diazepam
Clinical Impact:
Increased exposure of diazepam [see Clinical Pharmacology (12.3)].
Intervention:
Monitor patients for increased sedation and reduce the dose of diazepam as needed.
Digoxin
Clinical Impact:
Potential for increased exposure of digoxin [see Clinical Pharmacology (12.3)].
Intervention:
Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)
Clinical Impact:
Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
Intervention:
Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF [see Clinical Pharmacology (12.3)].
 
See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact:
Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions.
Intervention:
See Contraindications, Warnings and Precautions  in prescribing information for clarithromycin.
 
See Drug Interactions in prescribing information for amoxicillin.
Tacrolimus
Clinical Impact:
Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.
Intervention:
Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact:
Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions (5.10), Clinical Pharmacology (12.2)].
Intervention:
Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
Interaction with Secretin Stimulation Test
Clinical Impact:
Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention:
Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology (12.2)].
False Positive Urine Tests for THC
Clinical Impact:
There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.
Intervention:
An alternative confirmatory method should be considered to verify positive results.
Other
Clinical Impact:
There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram).
Intervention:
Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole.


Table name:
Concomitant Drug Name or Drug Class Clinical Rationale Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) The concomitant use of aripiprazole with strong CYP3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)] . With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)] .
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin) The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)] . With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)] .
Antihypertensive Drugs Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.8)] .
Benzodiazepines(e.g., lorazepam) The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.8)] . Monitor sedation and blood pressure. Adjust dose accordingly.


Table name:
a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
b = Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated
AED Co-administered 
AED Concentration
Topiramate Concentration
Phenytoin 
NC or 25% increasea
48% decrease
Carbamazepine (CBZ)
NC 
40% decrease
CBZ epoxideb
NC
NE
Valproic acid 
11% decrease
14% decrease
Phenobarbital
NC
NE
Primidone 
NC
NE
Lamotrigine 
NC at TPM doses up to 400 mg/day
13% decrease


Table name:
Interacting Drug Interaction
Theophylline Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin Monitor phenytoin level (7)
Methotrexate Monitor for methotrexate toxicity (7)
Cyclosporine May increase serum creatinine. Monitor serum creatinine (7)
Multivalent cation-containing products including antacids, metal cations or didanosine Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin (7)


Table name: Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology (12.3)]. Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see Clinical Pharmacology (12.3)]. There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole.
Table 3: Clinically Relevant Interactions Affecting Drugs Co-Administered with Omeprazole and Interaction with Diagnostics
Antiretrovirals
Clinical Impact:
The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known.
Intervention:
Rilpivirine-containing products: Concomitant use with omeprazole is contraindicated [see Contraindications (4)].
 
Atazanavir: Avoid concomitant use with omeprazole. See prescribing information for atazanavir for dosing information.
 
Nelfinavir: Avoid concomitant use with omeprazole. See prescribing information for nelfinavir.
 
Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities.
 
Other antiretrovirals: See prescribing information for specific antiretroviral drugs.
Warfarin
Clinical Impact:
Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
Intervention:
Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range.
Methotrexate
Clinical Impact:
Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions (5.11)].
Intervention:
A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate.
CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam)
Clopidogrel
Clinical Impact:
Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology (12.3)].
There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel.
Intervention:
Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy [see Warnings and Precautions (5.6)].
Citalopram
Clinical Impact:
Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology (12.3)].
Intervention:
Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.
Cilostazol
Clinical Impact:
Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology (12.3)].
Intervention:
Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.
Phenytoin
Clinical Impact:
Potential for increased exposure of phenytoin.
Intervention:
Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin.
Diazepam
Clinical Impact:
Increased exposure of diazepam [see Clinical Pharmacology (12.3)].
Intervention:
Monitor patients for increased sedation and reduce the dose of diazepam as needed.
Digoxin
Clinical Impact:
Potential for increased exposure of digoxin [see Clinical Pharmacology (12.3)].
Intervention:
Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)
Clinical Impact:
Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
Intervention:
Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF [see Clinical Pharmacology (12.3)].
 
See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact:
Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions.
Intervention:
See Contraindications, Warnings and Precautions  in prescribing information for clarithromycin.
 
See Drug Interactions in prescribing information for amoxicillin.
Tacrolimus
Clinical Impact:
Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.
Intervention:
Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact:
Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions (5.10), Clinical Pharmacology (12.2)].
Intervention:
Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
Interaction with Secretin Stimulation Test
Clinical Impact:
Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention:
Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology (12.2)].
False Positive Urine Tests for THC
Clinical Impact:
There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.
Intervention:
An alternative confirmatory method should be considered to verify positive results.
Other
Clinical Impact:
There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram).
Intervention:
Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole.


Table name:
 Concomitant Drug   Effect on
Concentration of
Lamotrigine or
Concomitant Drug
 Clinical Comment
Estrogen-containing oral contraceptivepreparation containing
30 mcg ethinylestradiol
and 150 mcg
levonorgestrel
 ↓ lamotrigine
 
 
 
↓ levonorgestrel
 Decreased lamotrigine levels approximately 50%.
 
 
Decrease in levonorgestrel component by 19%.
 Carbamazepine
and carbamazepine epoxide
 ↓ lamotrigine
 
 
 
? carbamazepine epoxide
 Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
 
May increase carbamazepine epoxide levels.
 Lopinavir/ritonavir  ↓ lamotrigine  Decreased lamotrigine concentration approximately 50%.
 Atazanavir/ritonavir  ↓ lamotrigine  Decreased lamotrigine AUC approximately 32%.
 Phenobarbital/primidone    ↓ lamotrigine  Decreased lamotrigine concentration approximately 40%.
 Phenytoin   ↓ lamotrigine  Decreased lamotrigine concentration approximately 40%.
 Rifampin   ↓ lamotrigine  Decreased lamotrigine AUC approximately 40%.
 Valproate   ↑ lamotrigine
 
 
 
? valproate
  Increased lamotrigine concentrations slightly more than 2-fold.
 
There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.


Table name:
 Interacting  Drug 
 Interaction 
 Multivalent cation-containing products including antacids, metal cations or didanosine 
 Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
 Warfarin 
 Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
 Antidiabetic agents 
 Carefully monitor blood glucose (5.11, 7.3)


Table name:
NA – Not available/reported
Digoxin concentrations increased greater than 50%
   Digoxin Serum   
Concentration Increase
   Digoxin AUC   
Increase
Recommendations
Amiodarone 70% NA Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring.
Captopril 58% 39%
Clarithromycin NA 70%
Dronedarone NA 150%
Gentamicin 129-212% NA
Erythromycin 100% NA
Itraconazole 80% NA
Nitrendipine 57% 15%
Propafenone NA 60-270%
Quinidine 100% NA
Ranolazine 50% NA
Ritonavir NA 86%
Tetracycline 100% NA
Verapamil 50-75% NA
Digoxin concentrations increased less than 50%
Atorvastatin 22% 15% Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring.
Carvedilol 16% 14%
Diltiazem 20% NA
Indomethacin 40% NA
Nefazodone 27% 15%
Nifedipine 45% NA
Propantheline 24% 24%
Quinine NA 33%
Saquinavir 27% 49%
Spironolactone      25% NA
Telmisartan 20-49% NA
Tolvaptan 30% NA
Trimethoprim 22-28% NA
Digoxin concentrations increased, but magnitude is unclear
Alprazolam, azithromycin, cyclosporine, diclofenac,
diphenoxylate, epoprostenol, esomeprazole, ibuprofen,
ketoconazole, lansoprazole, metformin, omeprazole,
rabeprazole,
Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin concentrations decreased
Acarbose, activated charcoal, albuterol, antacids, certain
cancer chemotherapy or radiation therapy, cholestyramine,
colestipol, extenatide, kaolin-pectin, meals high in bran,
metoclopramide, miglitol, neomycin, penicillamine,
phenytoin, rifampin, St. John’s Wort, sucralfate,
sulfasalazine
Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20-40% as necessary.
No significant Digoxin exposure changes
Please refer to section 12 for a complete list of drugs which     
were studied but reported no significant changes on digoxin exposure.
No additional actions are required.     


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may
result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-
   containing radiographic
   contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which
may result in hyperthyroidism
Amiodarone
Iodide (including iodine-
containing Radiographic
contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase Drugs that may decrease
serum TBG concentration serum TBG concentration
Clofibrate Androgens / Anabolic Steroids
Estrogen-containing oral Asparaginase
   contraceptives Glucocorticoids
Estrogens (oral) Slow-Release Nicotinic Acid
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal
Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake
Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
NITROPRUSSIDE
Para-aminosalicylate sodium
Perphenazine
Resorcinol
 (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Factors Dosage Adjustment of ABILIFY
Known CYP2D6 Poor Metabolizers Administer half of usual dose
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors Administer half of usual dose
Strong CYP2D6 and CYP3A4 inhibitors Administer a quarter of usual dose
Strong CYP3A4 inducers Double usual dose over 1 to 2 weeks


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir ) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Do not exceed 40 mg atorvastatin daily
Hepatitis C Protease inhibitor (boceprevir)


Table name:
 AED Co-administered  AED Concentration Topiramate
Concentration
 Phenytoin  NC or 25% increasea  48% decrease
 Carbamazepine (CBZ)  NC  40% decrease
 CBZ epoxideb  NC  NE
 Valproic acid  11% decrease  14% decrease
 Phenobarbital  NC  NE
 Primidone  NC  NE
 Lamotrigine  NC at TPM doses up to 400 mg/day  13% decrease
a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
b = Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated


Table name:
Antibiotics Anticonvulsants Other Drugs / Dietary Supplements
nafcillin carbamazepine bosentan St. John’s Wort
rifampin oxcarbazepine octreotide
phenobarbital orlistat
phenytoin sulfinpyrazone
terbinafine
ticlopidine


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 45.1, 7.1, 7.2, 7.3, 12.3)
   Interacting Agents    Prescribing Recommendations
   Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol
   Contraindicated with simvastatin
   Verapamil, diltiazem, dronedarone
   Do not exceed 10 mg simvastatin daily
   Amiodarone, amlodipine, ranolazine
   Do not exceed 20 mg simvastatin daily
   Grapefruit juice
   Avoid grapefruit juice


Table name:
Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin Tablets, USP
Drug(s) Recommendation Comments
Tizanidine Contraindicated Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications ( 4.2 )]
Theophylline Avoid Use
(Plasma Exposure Likely to be Increased and Prolonged)
Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate. [See Warnings and Precautions ( 5.6 ).]
Drugs Known to Prolong QT Interval Avoid Use Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions ( 5.10 ) and Use in
Specific Populations ( 8.5 )].
Oral antidiabetic drugs Use with caution Glucose-lowering effect potentiated Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs. [See Adverse Reactions (6.1).]
Phenytoin Use with caution Altered serum levels of phenytoin (increased and decreased) To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin with phenytoin.
Cyclosporine Use with caution (transient elevations in serum creatinine) Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs Use with caution (Increase in anticoagulant effect) The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole Use with caution Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin [see Warnings and Precautions (5.15)].
Clozapine Use with caution Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs Use with caution Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil Use with caution Two-fold increase in exposure Monitor for sildenafil toxicity (see Pharmacokinetics 12.3).
Duloxetine Avoid Use
Five-fold increase in duloxetine exposure
If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin Tablets, USP
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx®
(didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)
Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration. ( 2 )].
Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid
Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)
Potentiation of ciprofloxacin toxicity may occur.


Table name:
Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
↓ = Decreased (induces lamotrigine glucuronidation).
↑ = Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
Concomitant Drug 
Effect on Concentration of 
Lamotrigine or Concomitant Drug 
Clinical Comment 
Estrogen-containing oral 
contraceptive 
preparations containing 30 mcg 
ethinylestradiol and 150 mcg levonorgestrel 
↓ lamotrigine 

↓ levonorgestrel 
Decreased lamotrigine concentrations approximately 50%. 

Decrease in levonorgestrel component by 19%. 
Carbamazepine and carbamazepine epoxide 
↓ lamotrigine 


? carbamazepine epoxide 
Addition of carbamazepine decreases 
lamotrigine concentration approximately 40%. 
May increase carbamazepine epoxide levels. 
Lopinavir/ritonavir 
↓ lamotrigine 
Decreased lamotrigine concentration approximately 50%. 
Atazanavir/ritonavir 
↓ lamotrigine
Decreased lamotrigine AUC approximately 32%. 
Phenobarbital/Primidone 
↓ lamotrigine 
Decreased lamotrigine concentration
 approximately 40%. 
Phenytoin 
↓ lamotrigine 
Decreased lamotrigine concentration 
approximately 40%. 
Rifampin 
↓ lamotrigine 
Decreased lamotrigine AUC 
approximately 40%. 
Valproate 
↑ lamotrigine

 ? valproate 
Increased lamotrigine concentrations 
slightly more than 2-fold. 
There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.


Table name:
Interacting Drug Interaction
   Multivalent cation-containing products
   including antacids, metal cations or didanosine
   Absorption of levofloxacin is decreased when the tablet
   formulation  is taken within 2 hours of this product. (2.4, 7.1)
   Warfarin
   Effect may be enhanced. Monitor prothrombin time,
   INR, watch for bleeding (7.2)
   Antidiabetic agents
   Carefully monitor blood glucose (5.11, 7.3)


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4 , 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.12 , 7.3)


Table name:
Interacting Drug Interaction
Theophylline Serious and fatal reactions. Avoid concomitant use. Monitor serum level ( 7)
Warfarin Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding ( 7)
Antidiabetic agents Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose ( 7)
Phenytoin Monitor phenytoin level ( 7)
Methotrexate Monitor for methotrexate toxicity ( 7)
Cyclosporine May increase serum creatinine. Monitor serum creatinine ( 7)
Multivalent cation-containing products including antacids, metal cations or didanosine Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin ( 7)


Table name:
Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme
Inhibitors
Inducers
CYP2C9 
amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast
aprepitant, bosentan, carbamazepine, phenobarbital, rifampin 
CYP1A2 
acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton
montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking 
CYP3A4 
alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton
armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide 


Table name:
Figure 2: Effect of venlafaxine on the pharmacokinetics interacting drugs and their active metabolites.


Table name:
 Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
 Interacting Agents  Prescribing Recommendations
 Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)  Avoid atorvastatin
 HIV protease inhibitor (lopinavir plus ritonavir)  Use with caution and lowest dose necessary
 Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)  Do not exceed 20 mg atorvastatin daily
 HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
 Do not exceed 40 mg atorvastatin daily


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant  Drug
Effect  on  Concentration  of  Lamotrigine  or 
Concomitant  Drug
Clinical  Comment 
↓= Decreased (induces lamotrigine gluronidation).
↑= Increased (inhibits lamotrigine glucuronidation).
?= Conflicting data.
Estrogen-containing oral 
contraceptive preparations 
containing 30 mcg ethinylestradiol 
and 150 mcg levonorgestrel
↓ lamotrigine




Decreased lamotrigine levels 
approximately 50%.




↓ levonorgestrel
Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and 
CBZ epoxide
↓ lamotrigine

Addition of carbamazepine decreases lamotrigine 
concentration approximately 40%.


? CBZ epoxide
May increase CBZ epoxide levels
Phenobarbital/Primidone
↓ lamotrigine
Decreased lamotrigine 
concentration approximately 40%.
Phenytoin (PHT)
↓ lamotrigine
Decreased lamotrigine 
concentration approximately 40%
Rifampin
↓ lamotrigine
Decreased lamotrigine AUC 
approximately 40%
Valproate
↑ lamotrigine

Increased lamotrigine concentrations slightly 
more than 2-fold.


? valproate
Decreased valproate concentrations an average of 
25% over a 3-week period then stabilized in healthy volunteers; 
no change in controlled clinical trials in epilepsy patients.



Table name:
Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs  That  are  Affected  by  Ciprofloxacin 
Drug ( s
Recommendation
Comments
Tizanidine 
Contraindicated
Concomitant administration of tizanidine and  ciprofloxacin is contraindicated due to the  potentiation of hypotensive and sedative effects of  tizanidine [see CONTRAINDICATIONS (4.2)]
Theophylline 
Avoid Use 
(Plasma Exposure Likely to be 
Increased and Prolonged)
Concurrent administration of ciprofloxacin with  theophylline may result in increased risk of a patient  developing central nervous system (CNS) or other  adverse reactions. If concomitant use cannot be  avoided, monitor serum levels of theophylline and  adjust dosage as appropriate [see WARNINGS AND  PRECAUTIONS (5.9)].
Drugs Known to Prolong QT Interval 
Avoid Use
Ciprofloxacin may further prolong the QT interval in  patients receiving drugs known to prolong the QT  interval (for example, class IA or III antiarrhythmics,  tricyclic antidepressants, macrolides, antipsychotics)  [see WARNINGS AND PRECAUTIONS  (5.11) and USE IN SPECIFIC POPULATIONS (8.5)].
Oral antidiabetic drugs 
Use with caution Glucose-lowering 
effect potentiated
Hypoglycemia sometimes severe has been reported  when ciprofloxacin and oral antidiabetic agents,  mainly sulfonylureas (for example, glyburide,  glimepiride), were co-administered, presumably by  intensifying the action of the oral antidiabetic agent.  Fatalities have been reported. Monitor blood glucose  when ciprofloxacin is co-administered with oral  antidiabetic drugs [see ADVERSE REACTIONS (6.1)].
Phenytoin 
Use with caution 
Altered serum levels of 
phenytoin (increased and 
decreased)
To avoid the loss of seizure control associated with 
decreased phenytoin levels and to prevent phenytoin 
overdose-related adverse reactions upon 
ciprofloxacin discontinuation in patients receiving 
both agents, monitor phenytoin therapy, including 
phenytoin serum concentration during and shortly 
after co-administration of ciprofloxacin with phenytoin. 
Cyclosporine 
Use with caution 
(transient elevations in serum 
creatinine)
Monitor renal function (in particular serum 
creatinine) when ciprofloxacin is co-administered 
with cyclosporine. 
Anti-coagulant drugs 
Use with caution 
(Increase in anticoagulant 
effect)
The risk may vary with the underlying infection, age 
and general status of the patient so that the 
contribution of ciprofloxacin to the increase in INR 
(international normalized ratio) is difficult to assess. 
Monitor prothrombin time and INR frequently during 
and shortly after co-administration of ciprofloxacin 
with an oral anti-coagulant (for example, warfarin). 
Methotrexate 
Use with caution 
Inhibition of methotrexate renal 
tubular transport potentially 
leading to increased 
methotrexate plasma levels
Potential increase in the risk of methotrexate 
associated toxic reactions. Therefore, carefully 
monitor patients under methotrexate therapy when 
concomitant ciprofloxacin therapy is indicated. 
Ropinirole 
Use with caution
Monitoring for ropinirole-related adverse reactions  and appropriate dose adjustment of ropinirole is  recommended during and shortly after co- administration with ciprofloxacin [see WARNINGS  AND PRECAUTIONS (5.16)].
Clozapine 
Use with caution
Careful monitoring of clozapine associated adverse 
reactions and appropriate adjustment of clozapine 
dosage during and shortly after co-administration 
with ciprofloxacin are advised. 
NSAIDs 
Use with caution
Non-steroidal anti-inflammatory drugs (but not acetyl 
salicylic acid) in combination of very high doses of 
quinolones have been shown to provoke convulsions 
in pre-clinical studies and in postmarketing. 
Sildenafil 
Use with caution Two-fold increase in exposure
Monitor for sildenafil toxicity [see CLINICAL  PHARMACOLOGY 12.3].
Duloxetine 
Avoid Use
Five-fold increase in duloxetine exposure
If unavoidable, monitor for duloxetine toxicity 
Caffeine/Xanthine 
Derivatives 
Use with caution
Reduced clearance resulting in 
elevated levels and prolongation 
of serum half-life
Ciprofloxacin inhibits the formation of paraxanthine 
after caffeine administration (or pentoxifylline 
containing products). Monitor for xanthine toxicity 
and adjust dose as necessary. 
Drug ( s Affecting  Pharmacokinetics  of  Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products 
Containing Multivalent Cations (magnesium/aluminum 
antacids; polymeric phosphate binders (for example, 
sevelamer, lanthanum carbonate); sucralfate; Videx® 
(didanosine) chewable/buffered tablets or pediatric powder; 
other highly buffered drugs; or products containing 
calcium, iron, or zinc and dairy products) 
Ciprofloxacin should be taken at  least two hours before or six  hours after Multivalent cation- containing products  administration [see DOSAGE  AND ADMINISTRATION (2.4)]. Decrease ciprofloxacin absorption, resulting in lower 
serum and urine levels 
Probenecid 
Use with caution (interferes 
with renal tubular secretion of 
ciprofloxacin and increases 
ciprofloxacin serum levels)
Potentiation of ciprofloxacin toxicity may occur. 


Table name:
Table 6. Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Trials or Predicted Interactions [see Dosage and Administration (2)]
Concomitant Drug Class:
Drug Name
Effect on Concentration of Dolutegravir and/or Concomitant Drug Clinical Comment
HIV-1 Antiviral Agents
Non-nucleoside reverse transcriptase inhibitor: Etravirine a ↓Dolutegravir Use of TIVICAY with etravirine without coadministration of atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir is not recommended.
Non-nucleoside reverse transcriptase inhibitor: Efavirenz a ↓Dolutegravir Adjust dose of TIVICAY to 50 mg twice daily for treatment-naïve and treatment-experienced, INSTI-naïve adult patients. In pediatric patients, increase the weight-based dose to twice daily (Table 2). Use alternative combinations that do not include metabolic inducers where possible for INSTI-experienced patients with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance. b
Non-nucleoside reverse transcriptase inhibitor: Nevirapine ↓Dolutegravir Avoid coadministration with nevirapine because there are insufficient data to make dosing recommendations.
Protease inhibitor: Fosamprenavir/ritonavir a Tipranavir/ritonavir a ↓Dolutegravir Adjust dose of TIVICAY to 50 mg twice daily for treatment-naïve and treatment-experienced, INSTI-naïve adult patients. In pediatric patients, increase the weight-based dose to twice daily (Table 2). Use alternative combinations that do not include metabolic inducers where possible for INSTI-experienced patients with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance. b
Other Agents
Carbamazepine a ↓Dolutegravir Adjust dose of TIVICAY to 50 mg twice daily in treatment-naïve or treatment-experienced, INSTI-naïve adult patients. In pediatric patients, increase the weight-based dose to twice daily (Table 2). Use alternative treatment that does not include carbamazepine where possible for INSTI-experienced patients with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance. b
Oxcarbazepine
Phenytoin
Phenobarbital
St. John’s wort ( Hypericum perforatum)
↓Dolutegravir Avoid coadministration with TIVICAY because there are insufficient data to make dosing recommendations.
Medications containing polyvalent cations
(e.g., Mg or Al):
Cation-containing antacids a or laxatives
Sucralfate
Buffered medications
↓Dolutegravir Administer TIVICAY 2 hours before or 6 hours after taking medications containing polyvalent cations.
Oral calcium or iron supplements, including multivitamins containing calcium or iron a ↓Dolutegravir Administer TIVICAY 2 hours before or 6 hours after taking supplements containing calcium or iron. Alternatively, TIVICAY and supplements containing calcium or iron can be taken together with food.
Metformin ↑Metformin With concomitant use, limit the total daily dose of metformin to 1,000 mg either when starting metformin or TIVICAY. When stopping TIVICAY, the metformin dose may require an adjustment. Monitoring of blood glucose when initiating concomitant use and after withdrawal of TIVICAY is recommended.
Rifampin a ↓Dolutegravir Adjust dose of TIVICAY to 50 mg twice daily for treatment-naïve and treatment-experienced, INSTI-naïve adult patients. In pediatric patients, increase the weight-based dose to twice daily (Table 2). Use alternatives to rifampin where possible for INSTI-experienced patients with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance. b


Table name:
Inhibitors of CYP2D6
Clinical Impact: The concomitant use of tramadol hydrochloride and acetaminophen and CYP2D6 inhibitors may result in an increase in the plasma concentration of tramadol and a decrease in the plasma concentration of M1, particularly when an inhibitor is added after a stable dose of tramadol hydrochloride and acetaminophen is achieved. Since M1 is a more potent µ-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome.

After stopping a CYP2D6 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease and the M1 plasma concentration will increase which could increase or prolong therapeutic effects but also increase adverse reactions related to opioid toxicity, and may cause potentially fatal respiratory depression [see Clinical Pharmacology (12.3)].
Intervention: If concomitant use of a CYP2D6 inhibitor is necessary, follow patients closely for adverse reactions including opioid withdrawal, seizures and serotonin syndrome.

If a CYP2D6 inhibitor is discontinued, consider lowering tramadol hydrochloride and acetaminophen dosage until stable drug effects are achieved. Follow patients closely for adverse events including respiratory depression and sedation.
Examples Quinidine, fluoxetine, paroxetine and bupropion
Inhibitors of CYP3A4
Clinical Impact: The concomitant use of tramadol hydrochloride and acetaminophen and CYP3A4 inhibitors can increase the plasma concentration of tramadol and may result in a greater amount of metabolism via CYP2D6 and greater levels of M1. Follow patients closely for increased risk of serious adverse events including seizures and serotonin syndrome, and adverse reactions related to opioid toxicity including potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of tramadol hydrochloride and acetaminophen is achieved.

After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy and possibly signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol.
Intervention: If concomitant use is necessary, consider dosage reduction of tramadol hydrochloride and acetaminophen until stable drug effects are achieved. Follow patients closely for seizures and serotonin syndrome, and signs of respiratory depression and sedation at frequent intervals.

If a CYP3A4 inhibitor is discontinued, consider increasing the tramadol hydrochloride and acetaminophen dosage until stable drug effects are achieved and follow patients for signs and symptoms of opioid withdrawal.
Examples Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)
CYP3A4 Inducers
Clinical Impact: The concomitant use of tramadol hydrochloride and acetaminophen and CYP3A4 inducers can decrease the plasma concentration of tramadol [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to tramadol.

After stopping a CYP3A4 inducer, as the effects of the inducer decline, the tramadol plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression, seizures and serotonin syndrome.
Intervention: If concomitant use is necessary, consider increasing the tramadol hydrochloride and acetaminophen dosage until stable drug effects are achieved. Follow patients for signs of opioid withdrawal.

If a CYP3A4 inducer is discontinued, consider tramadol hydrochloride and acetaminophen dosage reduction and monitor for seizures and serotonin syndrome, and signs of sedation and respiratory depression.

Patients taking carbamazepine, a CYP3A4 inducer, may have a significantly reduced analgesic effect of tramadol. Because carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of tramadol hydrochloride, acetaminophen and carbamazepine is not recommended.
Examples: Rifampin, carbamazepine, phenytoin
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.6)].
Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue tramadol hydrochloride and acetaminophen if serotonin syndrome is suspected.
Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome [see Warnings and Precautions (5.7)] or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)].
Intervention: Do not use tramadol hydrochloride and acetaminophen in patients taking MAOIs or within 14 days of stopping such treatment.
Examples: phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact: May reduce the analgesic effect of tramadol hydrochloride and acetaminophen and/or precipitate withdrawal symptoms.
Intervention: Avoid concomitant use.
Examples: butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact: Tramadol may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of tramadol hydrochloride and acetaminophen and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when tramadol hydrochloride and acetaminophen is used concomitantly with anticholinergic drugs.
Digoxin
Clinical Impact: Post-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity.
Intervention: Follow patients for signs of digoxin toxicity and adjust dosage of digoxin as needed.
Warfarin
Clinical Impact: Post-marketing surveillance of tramadol has revealed rare reports of alteration of warfarin effect, including elevation of prothrombin times.
Intervention: Monitor the prothrombin time of patients on warfarin for signs of an interaction and adjust the dosage of warfarin as needed.


Table name:
Antibiotics Anticonvulsants Other Drugs/Dietary Supplements
nafcillin carbamazepine bosentan
rifampin oxcarbazepine octreotide
  phenobarbital orlistat
  phenytoin sulfinpyrazone
    St. John's Wort
    terbinafine
    ticlopidine


Table name:
Interacting DrugInteracting Drug InteractionInteraction
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products.
Warfarin
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( 7.2)
Antidiabetic agents
Carefully monitor blood glucose ( 5.11, 7.3)


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide

Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide






Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T and T levels and increase TSH, although all values remain within normal limits in most patients. 4 3
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate










Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
  Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration   Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen





Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid


Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)





Administration of these agents with levothyroxine results in an initial transient increase in FT . Continued administration results in a decrease in serum T and normal FT and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T and T to TBG and transthyretin. An initial increase in serum FT , is followed by return of FT to normal levels with sustained therapeutic serum salicylate concentrations, although total-T levels may decrease by as much as 30%. 4 4 4 4 3 4 4 4
  Drugs that may alter T 4 and T 3 metabolism
  Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin


Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. 4
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)




Administration of these enzyme inhibitors decrease the peripheral conversion of T to T , leading to decreased T levels. However, serum T levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T and T levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T concentrations by 30% with minimal change in serum T levels. However, long-term glucocorticoid therapy may result in slightly decreased T and T levels due to decreased TBG production (see above). 4 3 3 4 3 4 3 4 3 4
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives

Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)


Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin




Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2

Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin

Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of I, I, and Tc. 123 131 99m
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics









These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 23: Clinically Important Drug Interactions with Aripiprazole:
Concomitant  Drug  Name  or  Drug  Class

Clinical  Rationale

Clinical  Recommendation

Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine)
The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone  [ see  CLINICAL  PHARMACOLOGY  ( 12 . 3 )].
With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage  [ see  DOSAGE  AND  ADMINISTRATION ( 2 . 7 )].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)
The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone  [ see  CLINICAL  PHARMACOLOGY  ( 12 . 3 )].
With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage  [ see  DOSAGE  AND  ADMINISTRATION ( 2 . 7 )].
Antihypertensive Drugs
Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.
Monitor blood pressure and adjust dose accordingly  [ see  WARNINGS  AND  PRECAUTIONS  ( 5 . 7 )].
Benzodiazepines (e.g., lorazepam)
The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepamalone  [ see  WARNINGS  AND  PRECAUTIONS  ( 5 . 7 )]
Monitor sedation and blood pressure. Adjust dose accordingly.



Table name:
Table 5. Clinically-Significant Drug Interactions with Sertraline Hydrochloride
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:
The concomitant use of SSRIs including sertraline hydrochloride and MAOIs increases the risk of serotonin syndrome.
Intervention:
Sertraline hydrochloride is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [See Dosage and Administration (2.5), Contraindications (4), Warnings and Precautions (5.2)].
Examples:
selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue
Pimozide
Clinical Impact:
Increased plasma concentrations of pimozide, a drug with a narrow therapeutic index, may increase the risk of QT prolongation and ventricular arrhythmias.
Intervention:
Concomitant use of pimozide and sertraline hydrochloride is contraindicated [See Contraindications (4)].
Other Serotonergic Drugs
Clinical Impact:
The concomitant use of serotonergic drugs with sertraline hydrochloride increases the risk of serotonin syndrome.
Intervention:
Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of sertraline hydrochloride and/or concomitant serotonergic drugs [See Warnings and Precautions (5.2)].
Examples:
other SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort
Drugs that Interfere with Hemostasis (antiplatelet agents and anticoagulants)
Clinical Impact:
The concurrent use of an antiplatelet agent or anticoagulant with sertraline hydrochloride may potentiate the risk of bleeding.
Intervention:
Inform patients of the increased risk of bleeding associated with the concomitant use of sertraline hydrochloride and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio [See Warnings and Precautions (5.3)].
Examples:
aspirin, clopidogrel, heparin, warfarin
Drugs Highly Bound to Plasma Protein
Clinical Impact:
Sertraline hydrochloride is highly bound to plasma protein. The concomitant use of sertraline hydrochloride with another drug that is highly bound to plasma protein may increase free concentrations of sertraline hydrochloride or other tightly-bound drugs in plasma [See Clinical Pharmacology (12.3)].
Intervention:
Monitor for adverse reactions and reduce dosage of sertraline hydrochloride or other protein-bound drugs as warranted.
Examples:
warfarin
Drugs Metabolized by CYP2D6
Clinical Impact:
Sertraline hydrochloride is a CYP2D6 inhibitor [See Clinical Pharmacology (12.3)]. The concomitant use of sertraline hydrochloride with a CYP2D6 substrate may increase the exposure of the CYP2D6 substrate.
Intervention:
Decrease the dosage of a CYP2D6 substrate if needed with concomitant sertraline hydrochloride use. Conversely, an increase in dosage of a CYP2D6 substrate may be needed if sertraline hydrochloride is discontinued.
Examples:
propafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, thoridazine, tolterodine, venlafaxine
Phenytoin
Clinical Impact:
Phenytoin is a narrow therapeutic index drug. Sertraline hydrochloride may increase phenytoin concentrations.
Intervention:
Monitor phenytoin levels when initiating or titrating sertraline hydrochloride. Reduce phenytoin dosage if needed.
Examples:
phenytoin, fosphenytoin


Table name:
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on
Concentration of Lamotrigine or Concomitant Drug
Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine Decreased lamotrigine concentrations approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? carbamazepine epoxide May increase carbamazepine epoxide levels.
 Lopinavir/ritonavir ↓ lamotrigine Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir ↓ lamotrigine Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine
Increased lamotrigine concentrations slightly more than 2-fold.
? valproate There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.


Table name:
Table 5: Established Drug Interactions Based on Studies with Didanosine Delayed-Release Capsules or Studies with Buffered Formulations of Didanosine and Expected to Occur with Didanosine Delayed-Release Capsules
↑ Indicates increase.
↓ Indicates decrease.
Drug Effect Clinical Comment
ganciclovir ↑didanosine concentration If there is no suitable alternative to ganciclovir, then use in combination with didanosine delayed-release capsules with caution. Monitor for didanosine-associated toxicity.
methadone ↓didanosine concentration If coadministration of methadone and didanosine is necessary, the recommended formulation of didanosine is didanosine delayed-release capsules. Patients should be closely monitored for adequate clinical response when didanosine delayed-release capsules are coadministered with methadone, including monitoring for changes in HIV RNA viral load. Do not coadminister methadone with didanosine pediatric powder due to significant decreases in didanosine concentrations.
nelfinavir No interaction 1 hour after didanosine Administer nelfinavir 1 hour after didanosine delayed-release capsules.
tenofovir disoproxilfumarate ↑didanosine concentration A dose reduction of didanosine delayed-release capsules to the following dosage once daily taken together with tenofovir disoproxil fumarate and a light meal (400 kcalories or less and 20% fat or less ) or in the fasted state is recommended. 250 mg (adults weighing at least 60 kg with creatinine clearance of at least 60 mL/min) 200 mg (adults weighing less than 60 kg with creatinine clearance of at least 60 mL/min) Patients should be monitored for didanosine-associated toxicities and clinical response.


Table name:
Table 3 Clinically Significant Drug Interactions with Meloxicam
Drugs  that  Interfere  with  Hemostasis
Clinical  Impact :
Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.
Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention :
Monitor patients with concomitant use of meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ see  Warnings  and  Precautions  ( 5 . 11)].
Aspirin
Clinical  Impact :
Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ see  Warnings  and  Precautions  ( 5 . 2)].
Intervention :
Concomitant use of meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see  Warnings  and  Precautions  ( 5 . 11)].
Meloxicam is not a substitute for low dose aspirin for cardiovascular protection.
ACE  Inhibitors Angiotensin  Receptor  Blockers or  Beta - Blockers
Clinical  Impact :
NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).
In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, coadministration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention :
During concomitant use of meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.
During concomitant use of meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ see  Warnings  and  Precautions  ( 5 . 6 )].
When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical  Impact :
Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam.
Intervention :
During concomitant use of meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ see  Warnings  and  Precautions  ( 5 . 6)].
Lithium
Clinical  Impact :
NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [ see  Clinical  Pharmacology  ( 12 . 3)].
Intervention :
During concomitant use of meloxicam and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical  Impact :
Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention :
During concomitant use of meloxicam and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical  Impact :
Concomitant use of meloxicam and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention :
During concomitant use of meloxicam and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs  and  Salicylates
Clinical  Impact :
Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ see  Warnings  and  Precautions  ( 5 . 2)].
Intervention :
The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical  Impact :
Concomitant use of meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention :
During concomitant use of meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.
Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended.


Table name:
Drug Interactions Associated with Increased Risk of  Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice Avoid grapefruit juice


Table name:
AED Coadministered AED Concentration Topiramate Concentration
Phenytoin
NC or 25% increasePlasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
48% decrease


Carbamazepine (CBZ)
NC
40% decrease
CBZ epoxideIs not administered but is an active metabolite of carbamazepine.
NC
NE
Valproic acid
11% decrease
14% decrease
Phenobarbital
NC
NE
Primidone
NC
NE
Lamotrigine
NC at TPM doses up to 400 mg/day
13% decrease


Table name:
Interacting Drug Interaction
Theophylline Serious and fatal reactions. Avoid concomitant use. Monitor serum level ( 7)
Warfarin Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding ( 7)
Antidiabetic agents Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose ( 7)
Phenytoin Monitor phenytoin level ( 7)
Methotrexate Monitor for methotrexate toxicity ( 7)
Cyclosporine May increase serum creatinine. Monitor serum creatinine ( 7)
Multivalent cation-containing products including antacids, metal cations or didanosine Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin ( 7)


Table name:
Classes of Drugs    
also: diet high in vitamin K unreliable PT/INR determinations
   Adrenal Cortical Steroid Inhibitors     Antipsychotic Medications    Hypolipidemics
   Antacids    Antithyroid Drugs    Bile Acid-Binding Resins
   Antianxiety Agents
   Antiarrhythmics
   Barbiturates
   Diuretics
   HMG-CoA Reductase Inhibitors
   Anticonvulsants    Enteral Nutritional Supplements     Immunosuppressives
   Antidepressants    Fungal Medications, Systemic    Oral Contraceptives,
   Antihistamines    Gastric Acidity and Peptic  Ulcer Agents    Estrogen Containing
   Antineoplastics    Hypnotics    Selective Estrogen Receptor Modulators
   Steroids, Adrenocortical
   Tuberculosis Agents
   Vitamins
Specific Drugs Reported:    
   alcoholIncreased and decreased PT/INR responses have been reported.    warfarin sodium underdosage    phenytoin
   aminoglutethimide    cyclophosphamide    pravastatin
   amobarbital    dicloxacillin    prednisone
   atorvastatin    ethchlorvynol    primidone
   azathioprine    glutethimide    propylthiouracil
   butabarbital    griseofulvin    raloxifene
   butalbital    haloperidol    ranitidine
   carbamazepine    meprobamate    rifampin
   chloral hydrate    6-mercaptopurine    secobarbital
   chlordiazepoxide    methimazole    spironolactone
   chlorthalidone    moricizine hydrochloride    sucralfate
   cholestyramine    nafcillin    trazodone
   clozapine    paraldehyde    vitamin C (high dose)
   corticotropin    pentobarbital    vitamin K
   cortisone    phenobarbital


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7.1, 7.2, 7.3, 7.4)
Interacting Agents Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone Avoid simvastatin
Gemfibrozil, cyclosporine, danazol Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil Do not exceed 20 mg simvastatin daily
Diltiazem Do not exceed 40 mg simvastatin daily
Grapefruit juice Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Drug Description
Heparin Salicylate decreases platelet adhesivesness and interferes with hemostasis in heparin-treated patients
Pyrazinamide Inhibits pyrazinamide-induced hyperuricemia
Uricosuric Agents Effect of probenecid, sulfinpyrazone and phenylbutazone inhibited


Table name:
Interacting Agents Prescribing Recommendations 
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, gemfibrozil, cyclosporine,danazol Contraindicated with simvastatin 
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine  Do not exceed 20 mg simvastatin daily
Grapefruit juice Avoid grapefruit juice


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
↓ = Decreased (induces lamotrigine glucuronidation).
↑ = Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.     
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and
150 mcg levonorgestrel
↓ lamotrigine


↓ levonorgestrel
Decreased lamotrigine concentrations approximately 50%.

Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide ↓ lamotrigine



? carbamazepine epoxide
Addition of carbamazepine decreases lamotrigine concentration approximately 40%.

May increase carbamazepine epoxide levels.
Lopinavir/ritonavir ↓ lamotrigine Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir ↓ lamotrigine Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine


? valproate
Increased lamotrigine concentrations slightly more than 2-fold.

There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.


Table name:
Table 25: Clinically Important Drug Interactions with Aripiprazole:
Concomitant Drug Name or Drug Class

Clinical Rationale

Clinical Recommendation

Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine)
The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].
With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION(2.7 )].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)
The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3 )].
With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see DOSAGE AND ADMINISTRATION(2.7 )].
Antihypertensive Drugs
Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.
Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.8 )].
Benzodiazepines (e.g., lorazepam)
The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepamalone [see WARNINGS AND PRECAUTIONS (5.7)]
Monitor sedation and blood pressure. Adjust dose accordingly.



Table name:
Bleeding times
Clinical Impact: Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention: This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact: The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention: Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact: Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention: This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.


Table name:
Calcium Channel Antifungals Antibiotics Glucocorticoids Other Drugs
Blockers fluconazole azithromycin methylprednisolone allopurinol
diltiazem itraconazole clarithromycin amiodarone
nicardipine ketoconazole erythromycin bromocriptine
verapamil quinupristin/ colchicine
voriconazole dalfopristin
danazol
imatinib
metoclopramide
nefazodone
oral contraceptives


Table name:
Table 4: Clinically Relevant Interactions Affecting Omeprazole When Co-Administered with Other Drugs
CYP2C19 or CYP3A4 Inducers
Clinical Impact:
Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology (12.3)].
Intervention:
St. John’s Wort, rifampin: Avoid concomitant use with omeprazole [see Warnings and Precautions (5.9)].
Ritonavir-containing products: see prescribing information for specific drugs.
CYP2C19 or CYP3A4 Inhibitors
Clinical Impact:
Increased exposure of omeprazole [see Clinical Pharmacology (12.3)].
Intervention:
Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered.
 
See prescribing information for voriconazole.


Table name:
Table 2: Clinically Significant Drug Interactions with Sufentanil Citrate Injection
Inhibitors of CYP3A4
Clinical Impact: The concomitant use of Sufentanil Citrate Injection and CYP3A4 inhibitors can increase the plasma concentration of sufentanil, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of Sufentanil Citrate Injection is achieved [see Warnings and Precautions (5.4)].
After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the sufentanil plasma concentration will decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to sufentanil.
Intervention: If concomitant use is necessary, consider dosage reduction of Sufentanil Citrate Injection until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals.
If a CYP3A4 inhibitor is discontinued, consider increasing the Sufentanil Citrate Injection dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir), grapefruit juice
CYP3A4 Inducers
Clinical Impact: The concomitant use of Sufentanil Citrate Injection and CYP3A4 inducers can decrease the plasma concentration of sufentanil [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to sufentanil [see Warnings and Precautions (5.4)].
After stopping a CYP3A4 inducer, as the effects of the inducer decline, the sufentanil plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.
Intervention: If concomitant use is necessary, consider increasing the Sufentanil Citrate Injection dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider Sufentanil Citrate Injection dosage reduction and monitor for signs of respiratory depression.
Examples: Rifampin, carbamazepine, phenytoin
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact: The concomitant use of Sufentanil Citrate Injection with CNS depressants my result in decreased pulmonary artery pressure and may cause hypotension. Even small dosages of diazepam may cause cardiovascular depression when added to high dose or anesthetic dosages of Sufentanil Citrate Injection. As postoperative analgesia, concomitant use of Sufentanil Citrate Injection can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention: As postoperative analgesia, start with a lower dose of Sufentanil Citrate Injection and monitor patients for signs of respiratory depression, sedation, and hypotension. Fluids or other measures to counter hypotension should be available. [see Warnings and Precautions (5.5)].
Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Warnings and Precautions 5.5].
Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Sufentanil Citrate Injection if serotonin syndrome is suspected.
Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors
Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)].
Intervention: The use of Sufentanil Citrate Injection is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples: phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact: May reduce the analgesic effect of Sufentanil Citrate Injection and/or precipitate withdrawal symptoms.
Intervention: Avoid concomitant use.
Examples: butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact: Sufentanil may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Sufentanil Citrate Injection and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when Sufentanil Citrate Injection is used concomitantly with anticholinergic drugs.
Nitrous oxide
Clinical Impact: Nitrous oxide has been reported to produce cardiovascular depression when given with higher doses of Sufentanil Citrate Injection.
Intervention: Monitor patients for signs of cardiovascular depression that may be greater than otherwise expected.


Table name:
Table 6: Predicted Drug Interactions with Didanosine
↑ Indicates increase.
Drug or Drug Class Effect Clinical Comment
Drugs that may cause pancreatic toxicity ↑risk of pancreatitis Use only with extreme caution.Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that cause pancreatic toxicity is required, suspension of didanosine is recommended [see Warnings and Precautions (5.1)].
Neurotoxic drugs ↑risk of neuropathy Use with caution.[See Warnings and Precautions (5.5).]


Table name:
Table 4 Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table 5 for Magnitude of Interaction.
* The interaction between immediate-release VIRAMUNE and the drug was evaluated in a clinical study. The results of drug interaction studies with immediate-release VIRAMUNE are expected to also apply to VIRAMUNE XR.
Drug Name Effect on Concentration of Nevirapine or Concomitant Drug Clinical Comment
HIV Antiviral Agents: Protease Inhibitors (PIs)
Atazanavir/Ritonavir* ↓ Atazanavir

↑ Nevirapine
Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures.
Fosamprenavir* ↓Amprenavir

↑Nevirapine
Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.
Fosamprenavir/Ritonavir* ↓Amprenavir

↑Nevirapine
No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied.
Indinavir* ↓ Indinavir The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established.
Lopinavir/Ritonavir* ↓Lopinavir Dosing in adult patients:

A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.

Dosing in pediatric patients:

Please refer to the Kaletra® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.
Nelfinavir* ↓Nelfinavir M8 Metabolite
↓Nelfinavir Cmin
The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established.
Saquinavir/ritonavir The interaction between nevirapine and saquinavir/ritonavir has not been evaluated The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz* ↓ Efavirenz












The appropriate doses of these combinations with respect to safety and efficacy have not been established.




Delavirdine
Etravirine
Rilpivirine



Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial.










Other Agents
Analgesics:
Methadone*



↓ Methadone





Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal.  Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.



Antiarrhythmics:
Amiodarone, disopyramide, lidocaine
Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Antibiotics:
Clarithromycin*



↓ Clarithromycin

↑ 14-OH clarithromycin



Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased.  Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex , overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.



Rifabutin*



↑Rifabutin



Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.



Rifampin*



↓ Nevirapine



Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.



Anticonvulsants:
Carbamazepine, clonazepam, ethosuximide

Plasma concentrations of nevirapine and the anticonvulsant may be decreased.

Use with caution and monitor virologic response and levels of anticonvulsants.

Antifungals:
Fluconazole*



↑Nevirapine



Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events.



Ketoconazole*



↓ Ketoconazole



Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.



Itraconazole



↓ Itraconazole



Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug.



Antithrombotics:
Warfarin
Plasma concentrations may be decreased. Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.
Calcium channel blockers:
Diltiazem, nifedipine, verapamil
Plasma concentrations may be decreased. Appropriate doses for these combinations have not been established.
Cancer chemotherapy:
Cyclophosphamide
Plasma concentrations may be increased. Appropriate doses for this combination have not been established.
Ergot alkaloids:
Ergotamine
Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Immunosuppressants:
Cyclosporine, tacrolimus, sirolimus
Plasma concentrations may be decreased. Appropriate doses for these combinations have not been established.
Motility agents:
Cisapride
Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Opiate agonists:
Fentanyl
Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.
Oral contraceptives:
Ethinyl estradiol and Norethindrone*
↓ Ethinyl estradiol
↓ Norethindrone
Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended.


Table name:
Table 3 Established and Other Potentially SignificantThis table is not all inclusive. Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
Concomitant Drug Class: Drug Name Effect Clinical Comment
HIV antiviral agents
Protease inhibitor:
  atazanavir
↓atazanavir
↑ tenofovir
Coadministration of atazanavir with ATRIPLA is not recommended. Coadministration of atazanavir with either efavirenz or tenofovir DF decreases plasma concentrations of atazanavir. The combined effect of efavirenz plus tenofovir DF on atazanavir plasma concentrations is not known. Also, atazanavir has been shown to increase tenofovir concentrations. There are insufficient data to support dosing recommendations for atazanavir or atazanavir/ritonavir in combination with ATRIPLA.
Protease inhibitor:
  fosamprenavir
  calcium
↓ amprenavir Fosamprenavir (unboosted): Appropriate doses of fosamprenavir and ATRIPLA with respect to safety and efficacy have not been established.
Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when ATRIPLA is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when ATRIPLA is administered with fosamprenavir plus ritonavir twice daily.
Protease inhibitor:
  indinavir
↓ indinavir The optimal dose of indinavir, when given in combination with efavirenz, is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to efavirenz.
Protease inhibitor:
  lopinavir/ritonavir
↓ lopinavir
↑ tenofovir
Do not use once daily administration of lopinavir/ritonavir. Dose increase of lopinavir/ritonavir is recommended for all patients when coadministered with efavirenz. Refer to the full prescribing information for lopinavir/ritonavir for guidance on coadministration with efavirenz- or tenofovir-containing regimens, such as ATRIPLA. Patients should be monitored for tenofovir-associated adverse reactions.
Protease inhibitor:
  ritonavir
↑ ritonavir
↑ efavirenz
When ritonavir 500 mg every 12 hours was coadministered with efavirenz 600 mg once daily, the combination was associated with a higher frequency of adverse clinical experiences (e.g., dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when ATRIPLA is used in combination with ritonavir.
Protease inhibitor:
  saquinavir
↓ saquinavir Appropriate doses of the combination of efavirenz and saquinavir/ritonavir with respect to safety and efficacy have not been established.
CCR5 co-receptor antagonist:
  maraviroc
↓ maraviroc Efavirenz decreases plasma concentrations of maraviroc. Refer to the full prescribing information for maraviroc for guidance on coadministration with ATRIPLA.
NRTI:
  didanosine
↑ didanosine Coadministration of ATRIPLA and didanosine should be undertaken with caution, and patients receiving this combination should be monitored closely for didanosine-associated adverse reactions including pancreatitis, lactic acidosis, and neuropathy. A dose reduction of didanosine is recommended when coadministered with tenofovir DF. For additional information on coadministration with tenofovir DF-containing products, please refer to the didanosine prescribing information.
NNRTI:
  Other NNRTIs
↑ or ↓ efavirenz and/or NNRTI Combining two NNRTIs has not been shown to be beneficial. ATRIPLA contains efavirenz and should not be coadministered with other NNRTIs.
Integrase strand transfer inhibitor:
  raltegravir
↓ raltegravir Efavirenz reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.
Hepatitis C antiviral agents
Protease inhibitor:
  boceprevir
↓ boceprevir Plasma trough concentrations of boceprevir were decreased when boceprevir was coadministered with efavirenz, which may result in loss of therapeutic effect. The combination should be avoided.
Protease inhibitor:
  simeprevir
↓ simeprevir
↔ efavirenz
Concomitant administration of simeprevir with efavirenz is not recommended because it may result in loss of therapeutic effect of simeprevir.
NS5A inhibitors/NS5B polymerase inhibitors:
  ledipasvir/sofosbuvir
↑ tenofovir Patients receiving ATRIPLA and HARVONI® (ledipasvir/sofosbuvir) concomitantly should be monitored for adverse reactions associated with tenofovir DF.
  sofosbuvir/velpatasvir ↑ tenofovir
↓ velpatasvir
Coadministration of efavirenz-containing regimens and EPCLUSA® (sofosbuvir/velpatasvir) is not recommended.
Other agents
Anticoagulant:
  warfarin
↑ or ↓ warfarin Plasma concentrations and effects potentially increased or decreased by efavirenz.
Anticonvulsants:
  carbamazepine
↓ carbamazepine
↓ efavirenz
There are insufficient data to make a dose recommendation for ATRIPLA. Alternative anticonvulsant treatment should be used.
  phenytoin
  phenobarbital
↓ anticonvulsant
↓ efavirenz
Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted.
Antidepressants:
  bupropion
↓ buproprion The effect of efavirenz on bupropion exposure is thought to be due to the induction of bupropion metabolism. Increases in bupropion dosage should be guided by clinical response, but the maximum recommended dose of bupropion should not be exceeded.
  sertraline ↓ sertraline Increases in sertraline dose should be guided by clinical response.
Antifungals:
  itraconazole
↓ itraconazole
↓ hydroxy-itraconazole
Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered.
  ketoconazole ↓ ketoconazole Drug interaction trials with ATRIPLA and ketoconazole have not been conducted. Efavirenz has the potential to decrease plasma concentrations of ketoconazole.
  posaconazole ↓ posaconazole Avoid concomitant use unless the benefit outweighs the risks.
Anti-infective:
  clarithromycin
↓ clarithromycin
↑ 14-OH metabolite
Consider alternatives to macrolide antibiotics because of the risk of QT interval prolongation.
Antimycobacterial:
  rifabutin
↓ rifabutin Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week.
  rifampin ↓ efavirenz If ATRIPLA is coadministered with rifampin to patients weighing 50 kg or more, an additional 200 mg/day of efavirenz is recommended.
Antimalarials:
  artemether/lumefantrine
↓ artemether
↓ dihydroartemisinin
↓ lumefantrine
Consider alternatives to artemether/lumefantrine because of the risk of QT interval prolongation.
  atovaquone/proguanil ↓ atovaquone
↓ proguanil
Concomitant administration of atovaquone/proguanil with ATRIPLA is not recommended.
Calcium channel blockers:
  diltiazem
↓ diltiazem
↓ desacetyl diltiazem
↓ N-monodes-methyl diltiazem
Diltiazem dose adjustments should be guided by clinical response (refer to the full prescribing information for diltiazem). No dose adjustment of ATRIPLA is necessary when administered with diltiazem.
  Others (e.g., felodipine, nicardipine, nifedipine, verapamil) ↓ calcium channel blocker No data are available on the potential interactions of efavirenz with other calcium channel blockers that are substrates of CYP3A. The potential exists for reduction in plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response (refer to the full prescribing information for the calcium channel blocker).
HMG-CoA reductase inhibitors:
  atorvastatin
  pravastatin
  simvastatin
↓ atorvastatin
↓ pravastatin
↓ simvastatin
Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased with efavirenz. Consult the full prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose.
Hormonal contraceptives:
Oral:
  ethinyl
  estradiol/norgestimate
↓ active metabolites of norgestimate A reliable method of barrier contraception must be used in addition to hormonal contraceptives. Efavirenz had no effect on ethinyl estradiol concentrations, but progestin levels (norelgestromin and levonorgestrel) were markedly decreased. No effect of ethinyl estradiol/norgestimate on efavirenz plasma concentrations was observed.
Implant:
  etonogestrel
↓ etonogestrel A reliable method of barrier contraception must be used in addition to hormonal contraceptives. The interaction between etonogestrel and efavirenz has not been studied. Decreased exposure of etonogestrel may be expected. There have been postmarketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients.
Immunosuppressants:
  cyclosporine, tacrolimus, sirolimus, and others metabolized by CYP3A
↓ immuno-suppressant Decreased exposure of the immunosuppressant may be expected due to CYP3A induction by efavirenz. These immunosuppressants are not anticipated to affect exposure of efavirenz. Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with ATRIPLA.
Narcotic analgesic:
  methadone
↓ methadone Coadministration of efavirenz in HIV-1 infected individuals with a history of injection drug use resulted in decreased plasma levels of methadone and signs of opiate withdrawal. Methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms. Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms.


Table name:
Table 2: Drug — Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion -the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine / Dopamine
Agonists Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥100 mg/day or equivalent); Octreotide (>100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T4 and T3 serum transport — but FT4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone > 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.


Table name:
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact: Meperidine is contraindicated in patients who are receiving monoamine oxidase (MAOIs) or those who have recently received such agents. Therapeutic doses of meperidine have occasionally precipitated unpredictable, severe, and occasionally fatal reactions in patients who have received such agents within 14 days. The mechanism of these reactions is unclear, but may be related to a preexisting hyperphenylalaninemia. Some have been characterized by coma, severe respiratory depression, cyanosis, and hypotension, and have resembled the syndrome of acute narcotic overdose. Serotonin syndrome with agitation, hyperthermia, diarrhea, tachycardia, sweating, tremors and impaired consciousness may also occur. In other reactions the predominant manifestations have been hyperexcitability, convulsions, tachycardia, hyperpyrexia, and hypertension.
Intervention: Do not use meperidine hydrochloride tablets in patients taking MAOIs or within 14 days of stopping such treatment. Intravenous hydrocortisone or prednisolone have been used to treat severe reactions, with the addition of intravenous chlorpromazine in those cases exhibiting hypertension and hyperpyrexia. The usefulness and safety of narcotic antagonists in the treatment of these reactions is unknown.)
Examples: phenelzine, tranylcypromine, linezolid
Inhibitors of CYP3A4 and CYP2B6
Clinical Impact: The concomitant use of meperidine hydrochloride tablets and CYP3A4 or CYP2B6 inhibitors can increase the plasma concentration of meperidine, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of meperidine hydrochloride tablets and CYP2B6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of meperidine hydrochloride tablets is achieved [see Warnings and Precautions (5.4)]. After stopping a CYP3A4 or CYP2B6 inhibitor, as the effects of the inhibitor decline, the meperidine plasma concentration will decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to meperidine.
Intervention: If concomitant use is necessary, consider dosage reduction of meperidine hydrochloride tablets until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 or CYP2B6 inhibitor is discontinued, consider increasing the meperidine hydrochloride tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir)
CYP3A4 and CYP2B6 Inducers
Clinical Impact: The concomitant use of meperidine hydrochloride tablets and CYP3A4 or CYP2B6 inducers can decrease the plasma concentration of meperidine [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to meperidine [see Warningsand Precautions (5.4)]. After stopping a CYP3A4 or CYP2B6 inducer, as the effects of the inducer decline, the meperidine plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.
Intervention: If concomitant use is necessary, consider increasing the meperidine hydrochloride tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 or CYP2B6 inducer is discontinued, consider meperidine hydrochloride tablets dosage reduction and monitor for signs of respiratory depression.
Examples: Rifampin, carbamazepine, phenytoin
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.5)].
Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol
Serotonergic Drugs
Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Warnings and Precautions 5.8].
Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue meperidine hydrochloride tablets if serotonin syndrome is suspected.
Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase inhibitors (MAOIs) (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue)
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact: May reduce the analgesic effect of meperidine hydrochloride tablets and/or precipitate withdrawal symptoms.
Intervention: Avoid concomitant use.
Examples: butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact: Meperidine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of meperidine hydrochloride tablets and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when meperidine hydrochloride tablets is used concomitantly with anticholinergic drugs.
Acyclovir
Clinical Impact: The concomitant use of acyclovir may increase the plasma concentrations of meperidine and its metabolite, normeperidine.
Intervention: If concomitant use of acyclovir and meperidine hydrochloride tablets is necessary, monitor patients for respiratory depression and sedation at frequent intervals.
Cimetidine
Clinical Impact: The concomitant use of cimetidine may reduce the clearance and volume of distribution of meperidine also the formation of the metabolite, normeperidine, in healthy subjects.
Intervention: If concomitant use of cimetidine and meperidine hydrochloride tablets is necessary, monitor patients for respiratory depression and sedation at frequent intervals.


Table name:
Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme
Inhibitors
Inducers
CYP2C9 
amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast
aprepitant, bosentan, carbamazepine, phenobarbital, rifampin 
CYP1A2 
acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton
montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking 
CYP3A4 
alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton
armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide 


Table name:
Table 18Summary of Effect of Coadministered Drugs on Exposure to Active Moiety(Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients withSchizophrenia
*Change relative to reference
Coadministered Drug
Dosing Schedule

Effect on Active
Moiety
(Risperidone + 9-
Hydroxy-
Risperidone (Ratio*)

Risperidone Dose
Recommendation

Coadministered Drug
Risperidone
AUC
C m a x

Enzyme (CYP2D6) 
Inhibitors 





Fluoxetine 
20 mg/day
2 or 3 mg twice
daily
1.4
1.5
Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine 
10 mg/day
4 mg/day
1.3
-
Re-evaluate dosing. 

20 mg/day
4 mg/day
1.6
-
Do not exceed 8 mg/day

40 mg/day
4 mg/day
1.8
-

Enzyme (CYP3A/ 
PgP inducers) 





Carbamazepine 
573 ± 168 mg/day
3 mg twice daily
0.51
0.55
Titrate dose upwards.
Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) 
Inhibitors 





Ranitidine 
150 mg twice daily
1 mg single dose
1.2
1.4
Dose adjustment not
needed
Cimetidine 
400 mg twice daily
1 mg single dose
1.1
1.3
Dose adjustment not
needed
Erythromycin 
500 mg four times
daily
1 mg single dose
1.1
0.94
Dose adjustment not
needed
Other Drugs 





Amitriptyline 
50 mg twice daily
3 mg twice daily
1.2
1.1
Dose adjustment not
needed


Table name:
Table 7: Summary of AED Interactions with Oxcarbazepine
AED Coadministered Dose of AED (mg/day) Oxcarbazepine Dose (mg/day) Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval) Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine 400-2000 900 nc nc denotes a mean change of less than 10% 40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital 100-150 600-1800 14% increase [CI: 2% increase, 24% increase] 25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin 250-500 600-1800 >1200-2400 nc Pediatrics up to 40% increase Mean increase in adults at high oxcarbazepine doses [CI: 12% increase, 60% increase] 30% decrease [CI: 3% decrease, 48% decrease]
Valproic acid 400-2800 600-1800 nc 18% decrease [CI: 13% decrease, 40% decrease]


Table name:
Interacting  Drug
Interaction
Drugs known to prolong 
QT interval (e.g., Class IA 
and Class III antiarrhythmic 
agents).
Quinine sulfate prolongs  QT interval,  ECG abnormalities including  QT prolongation and  Torsades de Pointes.  Avoid concomitant use (5.3).
Other antimalarials 
(e.g., halofantrine, 
mefloquine).
ECG abnormalities including  QT prolongation Avoid concomitant  use (5.3, 7.2).
CYP3A4 inducers or 
inhibitors
Alteration in plasma  quinine concentration.  Monitor for lack of efficacy  or increased adverse events of  quinine (7.1).
CYP3A4 and 
CYP2D6 substrates
Quinine is an inhibitor of  CYP3A4 and CYP2D6.  Monitor for lack of efficacy  or increased adverse events  of the co-administered  drug (7.2).
Digoxin
Increased digoxin  plasma concentration (5.8, 7.1).


Table name: Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. During concomitant use of naproxen and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of naproxen and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS: Renal Toxicity and Hyperkalemia ). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Drugs That Interfere with Hemostasis
Clinical Impact:
Intervention: Monitor patients with concomitant use of naproxen with anticoagulants (e.g., warfarin-ephrine reuptake inhibitors (SNRIs)) for signs of bleeding (see WARNINGS: Hematologic Toxicity ).
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS: Gastrointestinal Bleeding, Ulceration and Perforation ).
Intervention: Concomitant use of naproxen and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS: Hematologic Toxicity ). Naproxen is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:
Intervention:
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention During concomitant use of naproxen with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS: Renal Toxicity and Hyperkalemia ).
Digoxin
Clinical Impact: The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of naproxen and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of naproxen and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of naproxen and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of naproxen and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS: Gastrointestinal Bleeding, Ulceration and Perforation ).
Intervention: The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of naproxen may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of naproxen and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact: Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention: Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen is not recommended.
Cholestyramine
Clinical Impact: Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention: Concomitant administration of cholestyramine with naproxen is not recommended.
Probenecid
Clinical Impact: Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention: Patients simultaneously receiving naproxen and probenecid should be observed for adjustment of dose if required.
Other Albumin-Bound Drugs
Clinical Impact: Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation ).
Intervention: Patients simultaneously receiving naproxen and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
 Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)  Avoid atorvastatin
 HIV protease inhibitor (lopinavir plus ritonavir)  Use with caution and lowest dose necessary
 Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)  Do not exceed 20 mg atorvastatin daily
 HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
 Do not exceed 40 mg atorvastatin daily


Table name:
 Interacting Agents  Prescribing Recommendations
 Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol  Contraindicated with simvastatin
 Verapamil, diltiazem, dronedarone   Do not exceed 10 mg simvastatin daily
 Amiodarone, amlodipine, ranolazine  Do not exceed 20 mg simvastatin daily
 Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin daily*
 Grapefruit juice  Avoid grapefruit juice


Table name:
Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s)
Recommendation
Comments
Tizanidine
Contraindicated
Concomitant administration of tizanidine and ciprofloxacin  is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2) ].
Theophylline
Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)
Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate. [See Warnings and Precautions (5.9) .]
Drugs Known to Prolong QT Interval
Avoid Use
 
Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see  Warnings and Precautions (5.11) and Use in   Specific Populations (8.5) ].
Oral antidiabetic drugs
Use with caution Glucose-lowering effect potentiated
Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs. [See Adverse Reactions (6.1) .]
Phenytoin
Use with caution Altered serum levels of phenytoin
(increased and decreased)
 
To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin with phenytoin.
Cyclosporine
Use with caution (transient elevations in serum creatinine)
Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs
Use with caution (Increase in anticoagulant effect)
The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate
Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels
Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole
Use with caution
Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin [see Warnings and Precautions (5.16) ].
Clozapine
Use with caution
Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs
Use with caution
Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies in and postmarketing.
Sildenafil
Use with caution Two-fold increase in exposure
Monitor for sildenafil toxicity (see Clinical Pharmacology (12.3 )].
Duloxetine
Avoid Use
Five-fold increase in duloxetine exposure
If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives
Use with caution Reduced clearance resulting in elevated levels and prolongation
of serum half-life
Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx® (didanosine) chewable/ buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)
Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2.4)] .
Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid
Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)
Potentiation of ciprofloxacin toxicity may occur.


Table name:
DRUG DESCRIPTION OF INTERACTION
Heparin Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparintreated patients.
Pyrazinamide Inhibits pyrazinamide induced hyperuricemia.
Uricosuric Agents Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited.


Table name:
Factors Dosage Adjustments for Aripiprazole
Known CYP2D6 Poor Metabolizers Administer half of usual dose
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors Administer half of usual dose
Strong CYP2D6 and CYP3A4 inhibitors Administer a quarter of usual dose
Strong CYP3A4 inducers Double usual dose over 1 to 2 weeks


Table name: Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol
Drug Interactions Associated with Increased Risk of  Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents Prescribing Recommendations
 
Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice Avoid grapefruit juice


Table name:
Table 8: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s) Recommendation Comments
Tizanidine Contraindicated Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2) ]
Theophylline Avoid Use (Plasma Exposure Likely to be Increased and Prolonged) Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions (5.6) ].
Drugs Known to Prolong QT Interval Avoid Use Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.10) and Use in Specific Populations (8.5) ].
Oral antibiotic drugs Use with caution Glucose-lowering effect potentiated Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs [see Adverse Reactions (6.1) ].
Phenytoin Use with caution Altered serum levels of phenytoin (increased and decreased) To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin with phenytoin.
Cyclosporine Use with caution (transient elevations in serum creatinine) Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs Use with caution (Increase in anticoagulant effect) The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anticoagulant (for example, warfarin).
Methotrexate Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole Use with caution Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin [see Warnings and Precautions (5.15) ].
Clozapine Use with caution Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs Use with caution Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil Use with caution Two-fold increase in exposure Monitor for sildenafil toxicity [see Clinical Pharmacology (12.3) ].
Duloxetine Avoid Use Five-fold increase in duloxetine exposure If unavoidable, monitor for duloxetine toxicity.
Caffeine/Xanthine Derivatives Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Probenecid Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels) Potentiation of ciprofloxacin toxicity may occur.


Table name:
Interacting Drug Interaction
   Multivalent cation-containing products
   including antacids, metal cations or didanosine
   Absorption of levofloxacin is decreased when the tablet
   formulation  is taken within 2 hours of this product. (2.4, 7.1)
   Warfarin
   Effect may be enhanced. Monitor prothrombin time,
   INR, watch for bleeding (7.2)
   Antidiabetic agents
   Carefully monitor blood glucose (5.12, 7.3)


Table name:
Inhibitors of CYP2D6
Clinical Impact: The concomitant use of tramadol HCl and acetaminophen and CYP2D6 inhibitors may result in an increase in the plasma concentration of tramadol and a decrease in the plasma concentration of M1, particularly when an inhibitor is added after a stable dose of tramadol HCl and acetaminophen is achieved. Since M1 is a more potent μ-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. After stopping a CYP2D6 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease and the M1 plasma concentration will increase which could increase or prolong therapeutic effects but also increase adverse reactions related to opioid toxicity, and may cause potentially fatal respiratory depression [see Clinical Pharmacology (12.3)].
Intervention: If concomitant use of a CYP2D6 inhibitor is necessary, follow patients closely for adverse reactions including opioid withdrawal, seizures and serotonin syndrome. If a CYP2D6 inhibitor is discontinued, consider lowering tramadol HCl and acetaminophen dosage until stable drug effects are achieved. Follow patients closely for adverse events including respiratory depression and sedation.
Examples Quinidine, fluoxetine, paroxetine and bupropion
Inhibitors of CYP3A4
Clinical Impact: The concomitant use of tramadol HCl and acetaminophen and CYP3A4 inhibitors can increase the plasma concentration of tramadol and may result in a greater amount of metabolism via CYP2D6 and greater levels of M1. Follow patients closely for increased risk of serious adverse events including seizures and serotonin syndrome, and adverse reactions related to opioid toxicity including potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of tramadol HCl and acetaminophen is achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy and possibly signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol.
Intervention: If concomitant use is necessary, consider dosage reduction of tramadol HCl and acetaminophen until stable drug effects are achieved. Follow patients closely for seizures and serotonin syndrome, and signs of respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the tramadol HCl and acetaminophen dosage until stable drug effects are achieved and follow patients for signs and symptoms of opioid withdrawal.
Examples Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)
CYP3A4 Inducers
Clinical Impact: The concomitant use of tramadol HCl and acetaminophen and CYP3A4 inducers can decrease the plasma concentration of tramadol [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to tramadol. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the tramadol plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression, seizures and serotonin syndrome.
Intervention: If concomitant use is necessary, consider increasing the tramadol HCl and acetaminophen dosage until stable drug effects are achieved. Follow patients for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider tramadol HCl and acetaminophen dosage reduction and monitor for seizures and serotonin syndrome, and signs of sedation and respiratory depression. Patients taking carbamazepine, a CYP3A4 inducer, may have a significantly reduced analgesic effect of tramadol. Because carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of tramadol HCl and acetaminophen and carbamazepine is not recommended.
Examples: Rifampin, carbamazepine, phenytoin
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.6)].
Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue tramadol HCl and acetaminophen if serotonin syndrome is suspected.
Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome [see Warnings and Precautions (5.7)] or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)].
Intervention: Do not use tramadol HCl and acetaminophen in patients taking MAOIs or within 14 days of stopping such treatment.
Examples: phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact: May reduce the analgesic effect of tramadol HCl and acetaminophen and/or precipitate withdrawal symptoms.
Intervention: Avoid concomitant use.
Examples: butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact: Tramadol may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of tramadol HCl and acetaminophen and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when tramadol HCl and acetaminophen is used concomitantly with anticholinergic drugs.
Digoxin
Clinical Impact: Post-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity.
Intervention: Follow patients for signs of digoxin toxicity and adjust dosage of digoxin as needed.
Warfarin
Clinical Impact: Post-marketing surveillance of tramadol has revealed rare reports of alteration of warfarin effect, including elevation of prothrombin times.
Intervention: Monitor the prothrombin time of patients on warfarin for signs of an interaction and adjust the dosage of warfarin as needed.


Table name:
Concomitant Drug Name or Drug Class
Clinical Rationale
Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) 
The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].
With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)
The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].
With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Antihypertensive Drugs
Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.
Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.7)]. 
Benzodiazepines (e.g., lorazepam)
The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.7)]
Monitor sedation and blood pressure. Adjust dose accordingly.


Table name:
Table 7: Summary of AED Interactions with Oxcarbazepine
AED Coadministered Dose of AED (mg/day) Oxcarbazepine Dose (mg/day) Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval) Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
 Carbamazepine
 400 to 2000
 900
 ncnc denotes a mean change of less than 10%
 40% decrease [CI: 17% decrease, 57% decrease]
 Phenobarbital
 100 to 150
 600 to 1800
 14% increase [CI: 2% increase, 24% increase]
 25% decrease [CI: 12% decrease, 51% decrease]
 Phenytoin
 250 to 500
 600 to 1800 >1200 to 2400
 nc Pediatrics
up to 40% increaseMean increase in adults at high oxcarbazepine doses [CI: 12% increase, 60% increase]
 30% decrease [CI: 3% decrease, 48% decrease]
 Valproic acid
 400 to 2800
 600 to 1800
 nc
 18% decrease [CI: 13% decrease, 40% decrease]


Table name:
Table 13 Established and Other Potentially Significant Drug Interactions
Concomitant Drug
Effect on Concentration of Lamotrigine or Concomitant Drug
Clinical Comment
↓ = Decreased (induces lamotrigine glucuronidation)
↑ = Increased (inhibits lamotrigine glucuronidation)
? = Conflicting data
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel
↓ lamotrigine
Decreased lamotrigine levels approximately 50%
↓ levonorgestrel
Decrease in levonorgestrel component by 19%
Carbamazepine (CBZ) and CBZ epoxide
↓ lamotrigine
Addition of carbamazepine decreases lamotrigine concentration approximately 40%
? CBZ epoxide
May increase CBZ epoxide levels.
Phenobarbital/Primidone
↓ lamotrigine
Decreased lamotrigine concentration approximately 40%
Phenytoin (PHT)
↓ lamotrigine
Decreased lamotrigine concentration approximately 40%
Rifampin
↓ lamotrigine
Decreased lamotrigine AUC approximately 40%
Valproate
↑ lamotrigine
Increased lamotrigine concentrations slightly more than 2-fold
? valproate
Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor
(boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Coadministered Drug Dosing Schedule Effect on Active Moiety (Risperidone + 9-Hydroxy- Risperidone) (Ratio*) Risperidone Dose Recommendation
Coadministered Drug Risperidone AUC Cmax
Enzyme (CYP2D6) Inhibitors    
Fluoxetine 20 mg/day 2 or 3 mg twice daily 1.4 1.5 Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine 10 mg/day 4 mg/day 1.3 - Re-evaluate dosing. Do not exceed 8 mg/day
  20 mg/day 4 mg/day 1.6 -
  40 mg/day 4 mg/day 1.8 -
Enzyme (CYP3A/ PgP inducers) Inducers          
Carbamazepine 573 ± 168 mg/day 3 mg twice daily 0.51 0.55 Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors          
Ranitidine 150 mg twice daily 1 mg single dose 1.2 1.4 Dose adjustment not needed
Cimetidine 400 mg twice daily 1 mg single dose 1.1 1.3 Dose adjustment not needed
Erythromycin 500 mg four times daily 1 mg single dose 1.1 0.94 Dose adjustment not needed
           
Other Drugs          
Amitriptyline 50 mg twice daily 3 mg twice daily 1.2 1.1 Dose adjustment not needed


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug
Effect on Concentration
of Lamotrigine or
Concomitant Drug
 
Clinical Comment
Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel
↓ lamotrigine
 
Decreased lamotrigine levels approximately 50%.
 
 
↓ levonorgestrel
Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide
↓ lamotrigine
Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
 
? CBZ epoxide
May increase CBZ epoxide levels
Phenobarbital/Primidone
↓ lamotrigine
Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)
↓ lamotrigine
Decreased lamotrigine concentration approximately 40%.
Rifampin
↓ lamotrigine
Decreased lamotrigine AUC approximately 40%.
Valproate
↑ lamotrigine
Increased lamotrigine concentrations slightly more than 2-fold.
 
? valproate
Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.
 


Table name:
Factors
Dosage  Adjustments  for  Aripiprazole  Tablets
Known CYP2D6 Poor Metabolizers
Administer half of usual dose
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors
Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors
Administer half of usual dose
Strong CYP2D6 and CYP3A4
inhibitors
Administer a quarter of usual dose
Strong CYP3A4 inducers
Double usual dose over 1 to 2 weeks


Table name:
Factors Dosage Adjustments for Aripiprazole
Known CYP2D6 Poor Metabolizers Administer half of usual dose
Known CYP2D6 Poor Metabolizersand strong CYP3A4 inhibitors Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors Administer half of usual dose
Strong CYP2D6 and CYP3A4inhibitors Administer a quarter of usual dose
Strong CYP3A4 inducers Double usual dose over 1 to 2 weeks


Table name:
AED  Co - administered
AED  Concentration
Topiramate 
Concentration

a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
b = Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated
Phenytoin
NC or 25% increase a
48% decrease
Carbamazepine (CBZ)
NC
40% decrease
CBZ epoxide b
NC
NE
Valproic acid
11% decrease
14% decrease
Phenobarbital
NC 
NE
Primidone
NC
NE
Lamotrigine
NC at TPM doses up to 400 mg/day
13% decrease



Table name:
Table 7  Summary of AED Interactions with Trileptal
AED
Coadministered
Dose of AED
(mg/day)
Trileptal Dose
(mg/day)
Influence of
Trileptal on AED
Concentration

(Mean Change,

90% Confidence

Interval)
Influence of
AED on MHD

Concentration

(Mean Change,

90% Confidence

Interval)
Carbamazepine 400-2000 900 nc1 40% decrease
[CI: 17% decrease,
57% decrease]
Phenobarbital 100-150 600-1800 14% increase
[CI: 2% increase,
24% increase]
25% decrease
[CI: 12% decrease,
51% decrease]
Phenytoin 250-500 600-1800
>1200-2400
nc1,2
up to 40%
increase3 
[CI: 12% increase,
60% increase]
30% decrease
[CI: 3% decrease,
48% decrease]
Valproic acid 400-2800 600-1800 nc1 18% decrease
[CI: 13% decrease,
40% decrease]


Table name:
Drugs that Affect
Renal Function
A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDs], COX-2 inhibitors may impair the excretion of digoxin.
Antiarrthymics Dofetilide Concomitant administration with digoxin was associated with a higher rate of torsades de pointes.
Sotalol Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
Dronedarone Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone Analog Teriparatide Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement Thyroid Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics Epinephrine Norepinephrine Dopamine Can increase the risk of cardiac arrhythmias.
Neuromuscular Blocking Agents Succinylcholine May cause sudden extrusion of potassium from muscle cells, causing arrhythmias in patients taking digoxin.
Supplements Calcium If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.


Table name:
Drugs that Affect Renal          
Function
A decline in GFR or tubular secretion, as from ACE inhibitors,          
angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs
[NSAIDs], COX-2 inhibitors may impair the excretion of digoxin.
Antiarrthymics Dofetilide Concomitant administration with digoxin was associated with a higher rate of torsades de pointes.
Sotalol Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
Dronedarone Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone
Analog
Teriparatide Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement Thyroid Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics Epinephrine Norepinephrine Dopamine Can increase the risk of cardiac arrhythmias.
Neuromuscular Blocking
Agents
Succinylcholine May cause sudden extrusion of potassium from muscle cells, causing arrhythmias in patients taking digoxin.
Supplements Calcium If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers
and calcium channel
blockers
Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.
Ivabradine Can increase the risk of bradycardia.


Table name:
Table III. Drugs That Have Been Documented Not to Interact With Theophylline or Drugs That Produce No Clinically Significant Interaction With TheophyllineRefer to  PRECAUTIONS Drug Interactions  for information regarding table.
albuterol,    systemic and inhaled amoxicillin ampicillin,    with or without sulbactam atenolol azithromycin caffeine,    dietary ingestion cefaclor co-trimoxazole    (trimethoprim and sulfamethoxazole) diltiazem dirithromycin enflurane famotidine felodipine finasteride hydrocortisone isoflurane isoniazid isradipine influenza vaccine ketoconazole lomefloxacin mebendazole medroxyprogesterone methylprednisolone metronidazole metoprolol nadolol nifedipine nizatidine norfloxacin ofloxacin omeprazole prednisone, prednisolone ranitidine rifabutin roxithromycin sorbitol   (purgative doses do not inhibit   theophylline absorption) sucralfate terbutaline, systemic terfenadine tetracycline tocainide


Table name:
Concomitant Drug Name or Drug Class Clinical Rationale Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) The concomitant use of aripiprazole with strong CYP3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)]. With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin) The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)]. With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Antihypertensive Drugs Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.7)].
Benzodiazepines(e.g., lorazepam) The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.7)]. Monitor sedation and blood pressure. Adjust dose accordingly.


Table name:
Interacting Drug Interaction
Drugs known to prolong QT interval (e.g., Class IA and Class III antiarrhythmic agents). Quinine sulfate capsules, USP prolongs QT interval, ECG abnormalities including QT prolongation and Torsades de Pointes. Avoid concomitant use (5.3).
Other antimalarials (e.g., halofantrine, mefloquine). ECG abnormalities including QT prolongation. Avoid concomitant use (5.3, 7.2).
CYP3A4 inducers or inhibitors Alteration in plasma quinine concentration. Monitor for lack of efficacy or increased adverse events of quinine (7.1).
CYP3A4 and CYP2D6 substrates Quinine is an inhibitor of CYP3A4 and CYP2D6. Monitor for lack of efficacy or increased adverse events of the co-administered drug (7.2).
Digoxin Increased digoxin plasma concentration (5.8, 7.1).


Table name:
Drugs That Interfere with Hemostasis
Clinical Impact: • Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of naproxen or naproxen sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: Concomitant use of naproxen or naproxen sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen or naproxen sodium is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE-inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: • During concomitant use of naproxen or naproxen sodium and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of naproxen or naproxen sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen or naproxen sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact: The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of naproxen or naproxen sodium and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen or naproxen sodium and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of naproxen or naproxen sodium and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of naproxen or naproxen sodium and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of naproxen or naproxen sodium and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of naproxen or naproxen sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of naproxen or naproxen sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact: Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention: Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen or naproxen sodium is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed release tablets are not recommended.
Cholestyramine
Clinical Impact: Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention: Concomitant administration of cholestyramine with naproxen or naproxen sodium is not recommended.
Probenecid
Clinical Impact: Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention: Patients simultaneously receiving naproxen or naproxen sodium and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact: Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention: Patients simultaneously receiving naproxen or naproxen sodium and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.


Table name:
Table 6: Effect of VYVANSE on Other Drugs
Concomitant Drug Name or Drug Class Clinical Rationale Clinical Recommendation
Monoamine Oxidase Inhibitors (MAOIs) Concomitant use of MAOIs and CNS stimulants can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure. Do not administer VYVANSE concomitantly or within 14 days after discontinuing MAOI treatment [see Contraindications (4)]


Table name:
Table 5. Clinically-Significant Drug Interactions with Sertraline Hydrochloride
Monoamine  Oxidase  Inhibitors  ( MAOIs )
Clinical  Impact :
The concomitant use of SSRIs including sertraline hydrochloride and MAOIs increases the risk of serotonin syndrome.
Intervention :
Sertraline hydrochloride is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue  [ See  Dosage  and  Administration  ( 2 . 5 ),  Contraindications  ( 4 ),  Warnings  and  Precautions  ( 5 . 2)].
Examples :
selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue
Pimozide
Clinical  Impact :
Increased plasma concentrations of pimozide, a drug with a narrow therapeutic index, may increase the risk of QT prolongation and ventricular arrhythmias.
Intervention :
Concomitant use of pimozide and sertraline hydrochloride is contraindicated  [ See  Contraindications  ( 4)].
Other  Serotonergic  Drugs
Clinical  Impact :
The concomitant use of serotonergic drugs with sertraline hydrochloride increases the risk of serotonin syndrome.
Intervention :
Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of sertraline hydrochloride and/or concomitant serotonergic drugs  [ See  Warnings  and  Precautions  ( 5 . 2)].
Examples :
other SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort
Drugs  that  Interfere  with  Hemostasis  ( antiplatelet  agents  and  anticoagulants )
Clinical  Impact :
The concurrent use of an antiplatelet agent or anticoagulant with sertraline hydrochloride may potentiate the risk of bleeding.
Intervention :
Inform patients of the increased risk of bleeding associated with the concomitant use of sertraline hydrochloride and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio  [ See  Warnings  and  Precautions  ( 5 . 3)].
Examples :
aspirin, clopidogrel, heparin, warfarin
Drugs  Highly  Bound  to  Plasma  Protein
Clinical  Impact :
Sertraline hydrochloride is highly bound to plasma protein. The concomitant use of sertraline hydrochloride with another drug that is highly bound to plasma protein may increase free concentrations of sertraline hydrochloride or other tightly-bound drugs in plasma  [ See  Clinical  Pharmacology  ( 12 . 3 )].
Intervention :
Monitor for adverse reactions and reduce dosage of sertraline hydrochloride or other protein-bound drugs as warranted.
Examples :
warfarin
Drugs  Metabolized  by  CYP2D6
Clinical  Impact :
Sertraline hydrochloride is a CYP2D6 inhibitor  [ See  Clinical  Pharmacology  ( 12 . 3)]. The concomitant use of sertraline hydrochloride with a CYP2D6 substrate may increase the exposure of the CYP2D6 substrate.
Intervention :
Decrease the dosage of a CYP2D6 substrate if needed with concomitant sertraline hydrochloride use. Conversely, an increase in dosage of a CYP2D6 substrate may be needed if sertraline hydrochloride is discontinued.
Examples :
propafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, thoridazine, tolterodine, venlafaxine
Phenytoin
Clinical  Impact :
Phenytoin is a narrow therapeutic index drug. Sertraline hydrochloride may increase phenytoin concentrations.
Intervention :
Monitor phenytoin levels when initiating or titrating sertraline hydrochloride. Reduce phenytoin dosage if needed.
Examples :
phenytoin, fosphenytoin


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
 Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration  Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
 Drugs that may alter T 4 and T 3 metabolism
 Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Interacting Drug
Interaction
Multivalent cation-containing
products including antacids,
metal cations or didanosine
Absorption of levofloxacin is decreased
when the tablet formulation is taken within
2 hours of these products. (2.4, 7.1)
Warfarin
Effect may be enhanced. Monitor
prothrombin time, INR, watch for bleeding
(7.2)
Antidibetic agents
Carefully monitor blood glucose (5.12, 7.3)


Table name:
Table III. Drugs That Have Been Documented Not to Interact With Theophylline or Drugs That Produce No Clinically Significant Interaction With TheophyllineRefer to  PRECAUTIONS Drug Interactions  for information regarding table.
albuterol,    systemic and inhaled amoxicillin ampicillin,    with or without sulbactam atenolol azithromycin caffeine,    dietary ingestion cefaclor co-trimoxazole    (trimethoprim and sulfamethoxazole) diltiazem dirithromycin enflurane famotidine felodipine finasteride hydrocortisone isoflurane isoniazid isradipine influenza vaccine ketoconazole lomefloxacin mebendazole medroxyprogesterone methylprednisolone metronidazole metoprolol nadolol nifedipine nizatidine norfloxacin ofloxacin omeprazole prednisone, prednisolone ranitidine rifabutin roxithromycin sorbitol   (purgative doses do not inhibit   theophylline absorption) sucralfate terbutaline, systemic terfenadine tetracycline tocainide


Table name:
Concomitant Drug Class: Drug Name Effect on Concentration of Amprenavir or Concomitant Drug Clinical Comment
HIV-Antiviral Agents
Non-nucleoside reverse transcriptase inhibitor: Efavirenza LEXIVA: ↓Amprenavir LEXIVA/ritonavir: ↓Amprenavir Appropriate doses of the combinations with respect to safety and efficacy have not been established. An additional 100 mg/day (300 mg total) of ritonavir is recommended when efavirenz is administered with LEXIVA/ritonavir once daily. No change in the ritonavir dose is required when efavirenz is administered with LEXIVA plus ritonavir twice daily.
Non-nucleoside reverse transcriptase inhibitor: Nevirapinea LEXIVA: ↓Amprenavir ↑Nevirapine LEXIVA/ritonavir: ↓Amprenavir ↑Nevirapine Coadministration of nevirapine and LEXIVA without ritonavir is not recommended. No dosage adjustment required when nevirapine is administered with LEXIVA/ritonavir twice daily. The combination of nevirapine administered with LEXIVA/ritonavir once-daily regimen has not been studied.
HIV protease inhibitor: Atazanavira LEXIVA: Interaction has not been evaluated. LEXIVA/ritonavir: ↓Atazanavir ↔Amprenavir Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV protease inhibitors: Indinavira, nelfinavira LEXIVA: ↑Amprenavir Effect on indinavir and nelfinavir is not well established. LEXIVA/ritonavir: Interaction has not been evaluated. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV protease inhibitors: Lopinavir/ritonavira ↓Amprenavir ↓Lopinavir An increased rate of adverse events has been observed. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV protease inhibitor: Saquinavira LEXIVA: ↓Amprenavir Effect on saquinavir is not well established. LEXIVA/ritonavir: Interaction has not been evaluated. Appropriate doses of the combination with respect to safety and efficacy have not been established.
Other Agents
Antiarrhythmics: Amiodarone, bepridil, lidocaine (systemic), and quinidine ↑Antiarrhythmics Use with caution. Increased exposure may be associated with life-threatening reactions such as cardiac arrhythmias. Therapeutic concentration monitoring, if available, is recommended for antiarrhythmics.
Anticoagulant: Warfarin Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants: Carbamazepine, phenobarbital, phenytoin Phenytoina LEXIVA: ↓Amprenavir LEXIVA/ritonavir: ↑Amprenavir ↓Phenytoin Use with caution. LEXIVA may be less effective due to decreased amprenavir plasma concentrations in patients taking these agents concomitantly. Plasma phenytoin concentrations should be monitored and phenytoin dose should be increased as appropriate. No change in LEXIVA/ritonavir dose is recommended.
Antidepressant: Paroxetine, trazodone ↓Paroxetine ↑Trazodone Coadministration of paroxetine with LEXIVA/ritonavir significantly decreased plasma levels of paroxetine. Any paroxetine dose adjustment should be guided by clinical effect (tolerability and efficacy). Concomitant use of trazodone and LEXIVA with or without ritonavir may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as LEXIVA, the combination should be used with caution and a lower dose of trazodone should be considered.
Antifungals: Ketoconazolea, itraconazole ↑Ketoconazole ↑Itraconazole Increase monitoring for adverse events. LEXIVA: Dose reduction of ketoconazole or itraconazole may be needed for patients receiving more than 400 mg ketoconazole or itraconazole per day. LEXIVA/ritonavir: High doses of ketoconazole or itraconazole (>200 mg/day) are not recommended.
Antimycobacterial: Rifabutina ↑Rifabutin and rifabutin metabolite A complete blood count should be performed weekly and as clinically indicated to monitor for neutropenia. LEXIVA: A dosage reduction of rifabutin by at least half the recommended dose is required. LEXIVA/ritonavir: Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (a maximum dose of 150 mg every other day or 3 times per week).
Benzodiazepines: Alprazolam, clorazepate, diazepam, flurazepam ↑Benzodiazepines Clinical significance is unknown. A decrease in benzodiazepine dose may be needed.
Calcium channel blockers: Diltiazem, felodipine, nifedipine, nicardipine, nimodipine, verapamil, amlodipine, nisoldipine, isradipine ↑Calcium channel blockers Use with caution. Clinical monitoring of patients is recommended.
Corticosteroid: Dexamethasone ↓Amprenavir Use with caution. LEXIVA may be less effective due to decreased amprenavir plasma concentrations.
Histamine H2-receptor antagonists: Cimetidine, famotidine, nizatidine, ranitidinea LEXIVA: ↓Amprenavir LEXIVA/ritonavir: Interaction not evaluated Use with caution. LEXIVA may be less effective due to decreased amprenavir plasma concentrations.
HMG-CoA reductase inhibitor: Atorvastatina, rosuvastatin ↑Atorvastatin ↑Rosuvastatin Use the lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as fluvastatin or pravastatin.
Immunosuppressants: Cyclosporine, tacrolimus, rapamycin ↑Immunosuppressants Therapeutic concentration monitoring is recommended for immunosuppressant agents.
Inhaled/nasal steroid: Fluticasone LEXIVA: ↑Fluticasone LEXIVA/ritonavir: ↑Fluticasone Use with caution. Consider alternatives to fluticasone, particularly for long-term use. May result in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushings syndrome and adrenal suppression have been reported during postmarketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone. Coadministration of fluticasone and LEXIVA/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.
Narcotic analgesic: Methadone ↓Methadone Data suggest that the interaction is not clinically relevant; however, patients should be monitored for opiate withdrawal symptoms.
Oral contraceptives: Ethinyl estradiol/norethin-dronea LEXIVA: ↓Amprenavir ↓Ethinyl estradiol LEXIVA/ritonavir: ↓Ethinyl estradiol Alternative methods of non-hormonal contraception are recommended. May lead to loss of virologic response. * Increased risk of transaminase elevations. No data are available on the use of LEXIVA/ritonavir with other hormonal therapies, such as hormone replacement therapy (HRT) for postmenopausal women.
PDE5 inhibitors: Sildenafil, tadalafil, vardenafil ↑Sildenafil ↑Tadalafil ↑Vardenafil May result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, visual changes, and priapism. LEXIVA: Sildenafil: 25 mg every 48 hours. Tadalafil: no more than 10 mg every 72 hours. Vardenafil: no more than 2.5 mg every 24 hours. LEXIVA/ritonavir: Sildenafil: 25 mg every 48 hours. Tadalafil: no more than 10 mg every 72 hours. Vardenafil: no more than 2.5 mg every 72 hours.
Proton pump inhibitors: Esomeprazolea, lansoprazole, omeprazole, pantoprazole, rabeprazole LEXIVA: ↔Amprenavir ↑Esomeprazole LEXIVA/ritonavir: ↔Amprenavir ↔Esomeprazole Proton pump inhibitors can be administered at the same time as a dose of LEXIVA with no change in plasma amprenavir concentrations.
Tricyclic antidepressants: Amitriptyline, imipramine ↑Tricyclics Therapeutic concentration monitoring is recommended for tricyclic antidepressants.


Table name:
TABLE 1. Clinically Significant Drug Interactions with DILAUDID INJECTION and/or DILAUDID-HP INJECTION
Benzodiazepines and other Central Nervous System Depressants (CNS)
Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines and other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.3)].
Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome
Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue DILAUDID INJECTION and DILAUDID-HP INJECTION if serotonin syndrome is suspected.
Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.3)].
If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
Intervention: The use of DILAUDID INJECTION or DILAUDID-HP INJECTION is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples: phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact: May reduce the analgesic effect of DILAUDID INJECTION and DILAUDID-HP INJECTION and/or precipitate withdrawal syndrome.
Intervention: Avoid concomitant use.
Examples: butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact: Hydromorphone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of DILAUDID INJECTION and DILAUDID-HP INJECTION and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when DILAUDID INJECTION and DILAUDID-HP INJECTION are used concomitantly with anticholinergic drugs.


Table name:
Drugs That Interfere with Hemostasis
Clinical Impact: Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of naproxen sodium tablets with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: Concomitant use of naproxen sodium tablets and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen sodium tablets are not substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: During concomitant use of naproxen sodium tablets and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of naproxen sodium tablets and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention During concomitant use of naproxen sodium tablets with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact: The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of naproxen sodium tablets and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen sodium tablets and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of naproxen sodium tablets and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of naproxen sodium tablets and cyclosporine may increase cyclosporine’s nephrotoxicity.  
Intervention: During concomitant use of naproxen sodium tablets and cyclosporine, monitor patients for signs of worsening renal function.  
NSAIDs and Salicylates  
Clinical Impact: Concomitant use of naproxen sodium tablets with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).  
Intervention: The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.  
Pemetrexed  
Clinical Impact: Concomitant use of naproxen sodium tablets and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).  
Intervention: During concomitant use of naproxen sodium tablets and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. 
Antacids and Sucralfate  
Clinical Impact: Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.  
Intervention: Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen sodium tablets are not recommended. Due to the gastric pH elevating effects of H 2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed-release tablets are not recommended.  
Cholestyramine  
Clinical Impact: Concomitant administration of cholestyramine can delay the absorption of naproxen.  
Intervention: Concomitant administration of cholestyramine with naproxen sodium tablets is not recommended.  
Probenecid  
Clinical Impact: Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.  
Intervention: Patients simultaneously receiving naproxen sodium tablets and probenecid should be observed for adjustment of dose if required.  
Other albumin-bound drugs  
Clinical Impact: Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.  
Intervention: Patients simultaneously receiving naproxen sodium tablets and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.  


Table name:
Table 14: Clinically Important Drug Interactions: Effect of other Drugs on Guanfacine Extended-Release Tablets
Concomitant Drug Name or Drug Class Clinical Rationale and Magnitude of Drug Interaction Clinical Recommendation
Strong and moderate CYP3A4 inhibitors, e.g., ketoconazole, fluconazole Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected resulting in an increase in exposure Consider dose reduction [see Dosage and administration (2.7) ]
Strong and moderate CYP3A4 inducers, e.g., rifampin, efavirenz Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected resulting in a 60% decrease in exposure Consider dose increase[see Dosage and administration (2.7) ]


Table name:
 Interacting Agents  Prescribing Recommendations
 Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)  Avoid atorvastatin
 HIV protease inhibitor (lopinavir plus ritonavir)  Use with caution and lowest dose necessary
 Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)  Do not exceed 20 mg atorvastatin daily
 HIV protease inhibitors (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
 Do not exceed 40 mg atorvastatin daily


Table name:
Table 4: Clinically Relevant Interactions Affecting Omeprazole When Co-Administered with Other Drugs
CYP2C19 or CYP3A4 Inducers
Clinical Impact:
Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology (12.3)].
Intervention:
St. John’s Wort, rifampin: Avoid concomitant use with omeprazole [see Warnings and Precautions (5.9)].
Ritonavir-containing products: see prescribing information for specific drugs.
CYP2C19 or CYP3A4 Inhibitors
Clinical Impact:
Increased exposure of omeprazole [see Clinical Pharmacology (12.3)].
Intervention:
Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered.
 
See prescribing information for voriconazole.


Table name:
Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s) Recommendation Comments
Tizanidine Contraindicated Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)]
Theophylline Avoid Use
(Plasma Exposure Likely to be Increased and Prolonged)
Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions (5.9)].
Drugs Known to Prolong QT Interval Avoid Use Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.11) and Use in Specific Populations (8.5)].
Oral antidiabetic drugs Use with caution
Glucose-lowering effect potentiated
Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs [see Adverse Reactions (6.1)].
Phenytoin Use with caution
Altered serum levels of phenytoin (increased and decreased)
To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin with phenytoin.
Cyclosporine Use with caution (transient elevations in serum creatinine) Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs Use with caution (Increase in anticoagulant effect) The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate Use with caution
Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels
Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole Use with caution Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin [see Warnings and Precautions (5.16)].
Clozapine Use with caution Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs Use with caution Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil Use with caution
Two-fold increase in exposure
Monitor for sildenafil toxicity [see Clinical Pharmacology (12.3)].
Duloxetine Avoid Use
Five-fold increase in duloxetine exposure
If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products) Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2.4)]. Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels) Potentiation of ciprofloxacin toxicity may occur.


Table name:
Interacting  Agents 
Prescribing  Recommendations 
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol 
Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone
Do not exceed 10 mg simvastatin daily 
Amiodarone, amlodipine, ranolazine
Do not exceed 20 mg simvastatin daily 
Grapefruit juice 
Avoid 
grapefruit juice 


Table name:
Calcium Channel Blockers Antifungals Antibiotics Glucocorticoids Other Drugs
diltiazem fluconazole azithromycin methylprednisolone allopurinol
nicardipine itraconazole clarithromycin amiodarone
verapamil ketoconazole erythromycin bromocriptine
voriconazole quinupristin/dalfopristin colchicine
danazol
imatinib
metoclopramide
nefazodone
oral contraceptives


Table name:
Table 25: Clinically Important Drug Interactions with ABILIFY:
Concomitant Drug Name or Drug Class Clinical Rationale Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) The concomitant use of ABILIFY with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of ABILIFY alone [see CLINICAL PHARMACOLOGY (12.3)]. With concomitant use of ABILIFY with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the ABILIFY dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin) The concomitant use of ABILIFY and carbamazepine decreased the exposure of aripiprazole compared to the use of ABILIFY alone [see CLINICAL PHARMACOLOGY (12.3)]. With concomitant use of ABILIFY with a strong CYP3A4 inducer, consider increasing the ABILIFY dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Antihypertensive Drugs Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.7)].
Benzodiazepines (e.g., lorazepam) The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.7)] Monitor sedation and blood pressure. Adjust dose accordingly.


Table name:
Table 3Drugs that Can Increase the Risk of Bleeding
Drug  Class
Specific  Drugs
Anticoagulants 
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin 
Antiplatelet Agents 
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine 
Nonsteroidal Anti-Inflammatory Agents 
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac 
Serotonin Reuptake Inhibitors 
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone 


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir ) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
*For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Interacting  Agents 
Prescribing  Recommendations 
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol 
Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone
Do not exceed 10 mg simvastatin daily 
Amiodarone, amlodipine, ranolazine
Do not exceed 20 mg simvastatin daily 
Lomitapide
For patients with HoFH, do not exceed 20 mg simvastatin daily*
Grapefruit juice 
Avoid grapefruit juice 


Table name:
Concomitant Drug Name or Drug Class Clinical Rationale Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., ketoconazole) or strong CYP2D6 inhibitors (e.g., paroxetine, fluoxetine) The concomitant use of oral aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole
[see CLINICAL PHARMACOLOGY (12.3)].
With concomitant use of ABILIFY MAINTENA with a strong CYP3A4 inhibitor or CYP2D6 inhibitor for more than 14 days, reduce the ABILIFY MAINTENA dosage
[see DOSAGE AND ADMINISTRATION (2.3)].
Strong CYP3A4 Inducers (e.g., carbamazepine) The concomitant use of oral aripiprazole and carbamazepine decreased the exposure of aripiprazole [see CLINICAL PHARMACOLOGY (12.3)]. Avoid use of ABILIFY MAINTENA in combination with carbamazepine and other inducers of CYP3A4 for greater than 14 days [see DOSAGE AND ADMINISTRATION (2.3)].
Antihypertensive Drugs Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.7)].
Benzodiazepines (e.g., lorazepam) The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.7)]. Monitor sedation and blood pressure. Adjust dose accordingly.


Table name:
Inhibitors of CYP2D6
Clinical Impact: The concomitant use of tramadol HCl and acetaminophen and CYP2D6 inhibitors may result in an increase in the plasma concentration of tramadol and a decrease in the plasma concentration of M1, particularly when an inhibitor is added after a stable dose of tramadol HCl and acetaminophen is achieved. Since M1 is a more potent μ-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. After stopping a CYP2D6 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease and the M1 plasma concentration will increase which could increase or prolong therapeutic effects but also increase adverse reactions related to opioid toxicity, and may cause potentially fatal respiratory depression [see Clinical Pharmacology (12.3)].
Intervention: If concomitant use of a CYP2D6 inhibitor is necessary, follow patients closely for adverse reactions including opioid withdrawal, seizures and serotonin syndrome. If a CYP2D6 inhibitor is discontinued, consider lowering tramadol HCl and acetaminophen dosage until stable drug effects are achieved. Follow patients closely for adverse events including respiratory depression and sedation.
Examples Quinidine, fluoxetine, paroxetine and bupropion
Inhibitors of CYP3A4
Clinical Impact: The concomitant use of tramadol HCl and acetaminophen and CYP3A4 inhibitors can increase the plasma concentration of tramadol and may result in a greater amount of metabolism via CYP2D6 and greater levels of M1. Follow patients closely for increased risk of serious adverse events including seizures and serotonin syndrome, and adverse reactions related to opioid toxicity including potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of tramadol HCl and acetaminophen is achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy and possibly signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol.
Intervention: If concomitant use is necessary, consider dosage reduction of tramadol HCl and acetaminophen until stable drug effects are achieved. Follow patients closely for seizures and serotonin syndrome, and signs of respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the tramadol HCl and acetaminophen dosage until stable drug effects are achieved and follow patients for signs and symptoms of opioid withdrawal.
Examples Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)
CYP3A4 Inducers
Clinical Impact: The concomitant use of tramadol HCl and acetaminophen and CYP3A4 inducers can decrease the plasma concentration of tramadol [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to tramadol. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the tramadol plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression, seizures and serotonin syndrome.
Intervention: If concomitant use is necessary, consider increasing the tramadol HCl and acetaminophen dosage until stable drug effects are achieved. Follow patients for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider tramadol HCl and acetaminophen dosage reduction and monitor for seizures and serotonin syndrome, and signs of sedation and respiratory depression. Patients taking carbamazepine, a CYP3A4 inducer, may have a significantly reduced analgesic effect of tramadol. Because carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of tramadol HCl and acetaminophen and carbamazepine is not recommended.
Examples: Rifampin, carbamazepine, phenytoin
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.6)].
Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue tramadol HCl and acetaminophen if serotonin syndrome is suspected.
Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome [see Warnings and Precautions (5.7)] or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)].
Intervention: Do not use tramadol HCl and acetaminophen in patients taking MAOIs or within 14 days of stopping such treatment.
Examples: phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact: May reduce the analgesic effect of tramadol HCl and acetaminophen and/or precipitate withdrawal symptoms.
Intervention: Avoid concomitant use.
Examples: butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact: Tramadol may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of tramadol HCl and acetaminophen and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when tramadol HCl and acetaminophen is used concomitantly with anticholinergic drugs.
Digoxin
Clinical Impact: Post-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity.
Intervention: Follow patients for signs of digoxin toxicity and adjust dosage of digoxin as needed.
Warfarin
Clinical Impact: Post-marketing surveillance of tramadol has revealed rare reports of alteration of warfarin effect, including elevation of prothrombin times.
Intervention: Monitor the prothrombin time of patients on warfarin for signs of an interaction and adjust the dosage of warfarin as needed.


Table name:
Drugs That Interfere with Hemostasis
Clinical Impact: • Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of naproxen or naproxen sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: Concomitant use of naproxen or naproxen sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen or naproxen sodium is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE-inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: • During concomitant use of naproxen or naproxen sodium and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of naproxen or naproxen sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen or naproxen sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact: The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of naproxen or naproxen sodium and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen or naproxen sodium and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of naproxen or naproxen sodium and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of naproxen or naproxen sodium and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of naproxen or naproxen sodium and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of naproxen or naproxen sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of naproxen or naproxen sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact: Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention: Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen or naproxen sodium is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed release tablets are not recommended.
Cholestyramine
Clinical Impact: Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention: Concomitant administration of cholestyramine with naproxen or naproxen sodium is not recommended.
Probenecid
Clinical Impact: Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention: Patients simultaneously receiving naproxen or naproxen sodium and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact: Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention: Patients simultaneously receiving naproxen or naproxen sodium and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.


Table name:
  Drugs That Interfere with Hemostasis
  Clinical Impact:  • Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
  Intervention:  Monitor patients with concomitant use of naproxen or naproxen sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
  Aspirin
  Clinical Impact:  Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
  Intervention:  Concomitant use of naproxen or naproxen sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen or naproxen sodium is not a substitute for low dose aspirin for cardiovascular protection.
  ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
  Clinical Impact:  • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE-inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
  Intervention:  • During concomitant use of naproxen or naproxen sodium and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of naproxen or naproxen sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
  Diuretics
  Clinical Impact:  Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
  Intervention:  During concomitant use of naproxen or naproxen sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
  Digoxin
  Clinical Impact:  The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
  Intervention:  During concomitant use of naproxen or naproxen sodium and digoxin, monitor serum digoxin levels.
  Lithium
  Clinical Impact:  NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
  Intervention:  During concomitant use of naproxen or naproxen sodium and lithium, monitor patients for signs of lithium toxicity.
  Methotrexate
  Clinical Impact:  Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
  Intervention:  During concomitant use of naproxen or naproxen sodium and methotrexate, monitor patients for methotrexate toxicity.
  Cyclosporine
  Clinical Impact:  Concomitant use of naproxen or naproxen sodium and cyclosporine may increase cyclosporine’s nephrotoxicity.
  Intervention:  During concomitant use of naproxen or naproxen sodium and cyclosporine, monitor patients for signs of worsening renal function.
  NSAIDs and Salicylates
  Clinical Impact:  Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
  Intervention:  The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
  Pemetrexed
  Clinical Impact:  Concomitant use of naproxen or naproxen sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
  Intervention:  During concomitant use of naproxen or naproxen sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
  Antacids and Sucralfate
  Clinical Impact:  Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
  Intervention:  Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen or naproxen sodium is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed release tablets are not recommended.
  Cholestyramine
  Clinical Impact:  Concomitant administration of cholestyramine can delay the absorption of naproxen.
  Intervention:  Concomitant administration of cholestyramine with naproxen or naproxen sodium is not recommended.
  Probenecid
  Clinical Impact:  Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
  Intervention:  Patients simultaneously receiving naproxen or naproxen sodium and probenecid should be observed for adjustment of dose if required.
  Other albumin-bound drugs
  Clinical Impact:  Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
  Intervention:  Patients simultaneously receiving naproxen or naproxen sodium and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.


Table name:
Table 3: Clinically Significant drug interactions with Celecoxib
Drugs  That  Interfere  with  Hemostasis
Clinical  Impact :
Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of Celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.
Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention :
Monitor patients with concomitant use of celecoxib capsules with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions ( 5.11)].
Aspirin
Clinical  Impact :
Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions ( 5.2)]. In two studies in healthy volunteers, and in patients with osteoarthritis and established heart disease respectively, celecoxib (200-400 mg daily) has demonstrated a lack of interference with the cardioprotective antiplatelet effect of aspirin (100-325 mg).
Intervention :
Concomitant use of celecoxib capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions ( 5.11)]. Celecoxib capsules are not a substitute for low dose aspirin for cardiovascular protection.
ACE  Inhibitors Angiotensin  Receptor  Blockers and  Beta - Blockers
Clinical  Impact :
NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).
In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention :
During concomitant use of celecoxib capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of celecoxib capsules and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions ( 5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical  Impact :
Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention :
During concomitant use of celecoxib capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions ( 5.6)].
Digoxin
Clinical  Impact :
The concomitant use of Celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention :
During concomitant use of celecoxib capsules and digoxin, monitor serum digoxin levels.
Lithium
Clinical  Impact :
NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention :
During concomitant use of celecoxib capsules and lithium, monitor patients for signs of lithium toxicity. 
Methotrexate 
Clinical  Impact :
Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). 

Celecoxib has no effect on methotrexate pharmacokinetics. 
Intervention :
During concomitant use of celecoxib capsules and methotrexate, monitor patients for methotrexate toxicity. 
Cyclosporine 
Clinical  Impact :
Concomitant use of celecoxib capsules and cyclosporine may increase cyclosporine’s nephrotoxicity. 
Intervention :
During concomitant use of celecoxib capsules and cyclosporine, monitor patients for signs of worsening renal function. 
NSAIDs  and  Salicylates 
Clinical  Impact :
Concomitant use of Celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions ( 5.2)].
Intervention :
The concomitant use of Celecoxib with other NSAIDs or salicylates is not recommended. 
Pemetrexed 
Clinical  Impact :
Concomitant use of celecoxib capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). 
Intervention :
During concomitant use of celecoxib capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. 

NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. 

In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. 
CYP2C9  Inhibitors  or  inducers 
Clinical  Impact :
Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Coadministration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of celecoxib. 
Intervention :
Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers. [see Clinical Pharmacology ( 12.3)].
CYP2D6  substrates 
Clinical  Impact :
In  vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is a potential for an  in  vivo drug interaction with drugs that are metabolized by CYP2D6 (e.g. atomoxetine), and celecoxib may enhance the exposure and toxicity of these drugs. 
Intervention :
Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2D6 substrates. [see Clinical Pharmacology ( 12.3)].
Corticosteroids 
Clinical  Impact :
Concomitant use of corticosteroids with celecoxib capsules may increase the risk of GI ulceration or bleeding. 
Intervention :
Monitor patients with concomitant use of celecoxib capsules with corticosteroids for signs of bleeding [see Warnings and Precautions ( 5.2)].


Table name:
Table 3 Clinically Significant Drug Interactions with Meloxicam
Drugs  that  Interfere  with  Hemostasis
Clinical  Impact :
Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.
Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention :
Monitor patients with concomitant use of meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ see  Warnings  and  Precautions  ( 5 . 11)].
Aspirin
Clinical  Impact :
Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ see  Warnings  and  Precautions  ( 5 . 2)].
Intervention :
Concomitant use of meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see  Warnings  and  Precautions  ( 5 . 11)].
Meloxicam is not a substitute for low dose aspirin for cardiovascular protection.
ACE  Inhibitors Angiotensin  Receptor  Blockers or  Beta - Blockers
Clinical  Impact :
NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).
In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, coadministration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention :
During concomitant use of meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.
During concomitant use of meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ see  Warnings  and  Precautions  ( 5 . 6 )].
When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical  Impact :
Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam.
Intervention :
During concomitant use of meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ see  Warnings  and  Precautions  ( 5 . 6)].
Lithium
Clinical  Impact :
NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [ see  Clinical  Pharmacology  ( 12 . 3)].
Intervention :
During concomitant use of meloxicam and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical  Impact :
Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention :
During concomitant use of meloxicam and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical  Impact :
Concomitant use of meloxicam and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention :
During concomitant use of meloxicam and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs  and  Salicylates
Clinical  Impact :
Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ see  Warnings  and  Precautions  ( 5 . 2)].
Intervention :
The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical  Impact :
Concomitant use of meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention :
During concomitant use of meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.
Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended.


Table name:
Table 1: Drugs that may have their plasma concentrations increased by itraconazole
Drug Class
Contraindicated
Not Recommended
Use with Caution
Comments
 
Under no circumstances is the drug to be coadministered with itraconazole, and up to two weeks after discontinuation of treatment with itraconazole.
 
It is recommended that the use of the drug be avoided during and up to two weeks after discontinuation of treatment with itraconazole, unless the benefits outweigh the potentially increased risks of side effects. If coadministration cannot be avoided, clinical monitoring for signs or symptoms of increased or prolonged effects or side effects of the interacting drug is recommended, and its dosage be reduced or interrupted as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured. The label of the coadministered drug should be consulted for information on dose adjustment and adverse effects.
Careful monitoring is recommended when the drug is coadministered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of the interacting drug, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured. The label of the coadministered drug should be consulted for information on dose adjustment and adverse effects.
 
Alpha Blockers
 
tamsulosin
 
 
Analgesics
 
methadone
 
 
alfentanil,
buprenorphine IV and sublingual,
fentanyl,
oxycodone,
sufentanil
 
Methadone: The potential increase in plasma concentrations of methadone when coadministered with itraconazole may increase the risk of serious cardiovascular events including QTc prolongation and torsade de pointes.
Fentanyl: The potential increase in plasma concentrations of fentanyl when coadministered with itraconazole may increase the risk of potentially fatal respiratory depression.
Sufentanil: No human pharmacokinetic data of an interaction with itraconazole are available. In vitro data suggest that sufentanil is metabolized by CYP3A4 and so potentially increased sufentanil plasma concentrations would be expected when coadministered with itraconazole.
Antiarrhythmics
disopyramide,
dofetilide,
dronedarone,
quinidine
 
digoxin
Disopyramide, dofetilide, dronedarone, quinidine: The potential increase in plasma concentrations of these drugs when coadministered with itraconazole may increase the risk of serious cardiovascular events including QTc prolongation.
Antibacterials
 
telithromycin, in subjects with severe renal impairment or severe hepatic impairment
rifabutin
telithromycin
Telithromycin: The potential increase in plasma concentrations of telithromycin in subjects with severe renal impairment or severe hepatic impairment, when coadministered with itraconazole may increase the risk of serious cardiovascular events including QT prolongation and torsade de pointes.
Rifabutin: See also under ‘Drugs that may decrease itraconazole plasma concentrations’.
Anticoagulants and Antiplatelet Drugs
ticagrelor
apixaban,
rivaroxaban
coumarins,
cilostazol,
dabigatran
Ticagrelor: The potential increase in plasma concentrations of ticagrelor may increase the risk of bleeding.
Coumarins: Itraconazole may enhance the anticoagulant effect of coumarin-like drugs, such as warfarin.
Anticonvulsants
 
carbamazepine
 
Carbamazepine: In vivo studies have demonstrated an increase in plasma carbamazepine concentrations in subjects concomitantly receiving ketoconazole. Although there are no data regarding the effect of itraconazole on carbamazepine metabolism, because of the similarities between ketoconazole and itraconazole, concomitant administration of itraconazole and carbamazepine may inhibit the metabolism of carbamazepine. See also under ‘Drugs that may decrease itraconazole plasma concentrations’.
Antidiabetics
 
 
repaglinide,
saxagliptin
 
Antihelmintics and Antiprotozoals
 
 
praziquantel
 
Antimigraine Drugs
 
ergot alkaloids, such as dihydroergotamine, ergometrine (ergonovine), ergotamine, methylergometrine (methylergonovine)
 
 
eletriptan
Ergot Alkaloids: The potential increase in plasma concentrations of ergot alkaloids when coadministered with itraconazole may increase the risk of ergotism, i.e., a risk for vasospasm potentially leading to cerebral ischemia and/or ischemia of the extremities.
Antineoplastics
irinotecan
axitinib,
dabrafenib,
dasatinib,
ibrutinib,
nilotinib,
sunitinib
 
bortezomib,
busulphan,
docetaxel,
erlotinib,
imatinib,
ixabepilone,
lapatinib,
ponatinib,
trimetrexate,
vinca alkaloids
Irinotecan: The potential increase in plasma concentrations of irinotecan when coadministered with itraconazole may increase the risk of potentially fatal adverse events.
 
Antipsychotics,
Anxiolytics and Hypnotics
lurasidone,
oral midazolam,
pimozide,
triazolam
 
alprazolam,
aripiprazole,
buspirone,
diazepam,
haloperidol,
midazolam IV,
perospirone,
quetiapine,
ramelteon,
risperidone
Midazolam, triazolam:
Coadministration of itraconazole and oral midazolam, or triazolam may cause several-fold increases in plasma concentrations of these drugs. This may potentiate and prolong hypnotic and sedative effects, especially with repeated dosing or chronic administration of these agents.
Pimozide: The potential increase in plasma concentrations of pimozide when coadministered with itraconazole may increase the risk of serious cardiovascular events including QTc prolongation and torsade de pointes.
Antivirals
 
 
simeprevir
 
maraviroc,
indinavir,
ritonavir,
saquinavir
Indinavir, ritonavir: See also under ‘Drugs that may increase itraconazole plasma concentrations’.
Beta Blockers
 
 
nadolol
 
Calcium Channel
Blockers
felodipine,
nisoldipine
 
other dihydropyridines,
verapamil
 
Calcium channel blockers canhave a negative inotropic effect which may be additive to those of itraconazole. The potential increase in plasma concentrations of calcium channel blockers when co-administered with itraconazole may increase the risk of congestive heart failure.
Dihydropyridines: Concomitant administration of itraconazole may cause several-fold increases in plasma concentrations of dihydropyridines. Edema has been reported in patients concomitantly receiving itraconazole and dihydropyridine calcium channel blockers.
Cardiovascular Drugs, Miscellaneous
ranolazine
aliskiren,
sildenafil, for the treatment of pulmonary hypertension
bosentan,
riociguat
Ranolazine: The potential increase in plasma concentrations of ranolazine when coadministered with itraconazole may increase the risk of serious cardiovascular events including QTc prolongation.
Diuretics
eplerenone
 
 
Eplerenone: The potential increase in plasma concentrations of eplerenone when coadministered with itraconazole may increase the risk of hyperkalemia and hypotension.
Gastrointestinal Drugs
cisapride
 
aprepitant
 
Cisapride: The potential increase in plasma concentrations of cisapride when coadministered with itraconazole may increase the risk of serious cardiovascular events including QTc prolongation.
 
 
 
 
 
Immunosuppres
sants
 
everolimus,
temsirolimus
budesonide,
ciclesonide,
cyclosporine,
dexamethasone,
fluticasone, methylprednisolone,
rapamycin (also known as sirolimus),
tacrolimus
 
Lipid Regulating Drugs
lovastatin,
simvastatin
 
atorvastatin
The potential increase in plasma concentrations of atorvastatin, lovastatin, and simvastatin when coadministered with itraconazole may increase the risk of skeletal muscle toxicity, including rhabdomyolysis.
Respiratory Drugs
 
salmeterol
 
 
Urological Drugs
fesoterodine, in subjects with moderate to severe renal impairment, or moderate to severe hepatic impairment, solifenacin, in subjects with severe renal impairment or moderate to severe hepatic impairment
darifenacin,
vardenafil
fesoterodine.
oxybutynin,
sildenafil, for the treatment of erectile dysfunction,
solifenacin,
tadalafil,
tolterodine
Fesoterodine: The potential increase in plasma concentrations of the fesoterodine active metabolite may be greater in subjects with moderate to severe renal impairment, or moderate to severe hepatic impairment, which may lead to an increased risk of adverse reactions.
Solifenacin: The potential increase in plasma concentrations of solifenacin in subjects with severe renal impairment or moderate to severe hepatic impairment, when coadministered with itraconazole may increase the risk of serious cardiovascular events including QT prolongation.
Other
colchicine, in subjects with renal or hepatic impairment
colchicine, conivaptan, tolvaptan
cinacalcet
Colchicine: The potential increase in plasma concentrations of colchicine when coadministered with itraconazole may increase the risk of potentially fatal adverse events.
Conivaptan and Tolvaptan: A safe and effective dose of either conivaptan or tolvaptan has not been established when coadministered with itraconazole.


Table name:
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine Decreased lamotrigine concentrations approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? carbamazepine epoxide May increase carbamazepine epoxide levels.
Lopinavir/ritonavir ↓ lamotrigine Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir ↓ lamotrigine Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine Increased lamotrigine concentrations slightly more than 2-fold.
? valproate There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.


Table name:
Drugs that Affect Renal Function A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDS], COX-2 inhibitors may impair the excretion of digoxin.
Antiarrthymics Dofetilide Concomitant administration with digoxin was associated with a higher rate of torsades de pointes
Sotalol Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
Dronedarone Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone Analog Teriparatide Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement Thyroid Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics Epinephrine
Norepinephrine     
Dopamine
Can increase the risk of cardiac arrhythmias
Neuromuscular Blocking Agents      Succinylcholine May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.
Supplements Calcium If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T 4 and T 3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin/Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens/Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non-Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT 4 . Continued administration results in a decrease in serum T 4 and normal FT 4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T 4 and T 3 to TBG and transthyretin. An initial increase in serum FT 4 is followed by return of FT 4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T 4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T 4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ³ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T 4 to T 3, leading to decreased T 3 levels. However, serum T 4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T 3 and T 4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T 3 concentrations by 30% with minimal change in serum T 4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T 3 and T 4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias
and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123 I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol                                       Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin daily*
Grapefruit juice Avoid grapefruit juice


Table name:
Table 1: Clinically Significant Drug Interactions with MS CONTIN
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.4)].
Examples: Benzodiazepines and other sedative hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue MS CONTIN if serotonin syndrome is suspected.
Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.6)].
Intervention: Do not use MS CONTIN in patients taking MAOIs or within 14 days of stopping such treatment.
Examples: phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact: May reduce the analgesic effect of MS CONTIN and/or precipitate withdrawal symptoms.
Intervention: Avoid concomitant use.
Examples: butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact: Morphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of MS CONTIN and/or the muscle relaxant as necessary.
Cimetidine
Clinical Impact: The concomitant use of cimetidine can potentiate morphine effects and increase risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of MS CONTIN and/or cimetidine as necessary.
Diuretics
Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when MS CONTIN is used concomitantly with anticholinergic drugs.
P-Glycoprotein (P-gp) Inhibitors
Clinical Impact: The concomitant use of PGP-inhibitors can increase the exposure to morphine by about two-fold and can increase risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of MS CONTIN and/or the PGP-inhibitor as necessary.
Example: Quinidine


Table name:
Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
*Change relative to reference
Coadministered Drug
 
Dosing Schedule
Effect on Active Moiety
(Risperidone + 9- Hydroxy-
Risperidone (Ratio*)
Risperidone Dose
Recommendation
Coadministered Drug
Risperidone
AUC
Cmax
Enzyme (CYP2D6)inhibitors
 
 
 
 
Fluoxetine
20 mg/day
2 or 3 mg twice daily
1.4
1.5

Re-evaluate dosing.
Do not exceed 8 mg/day
Paroxetine
10 mg/day
4 mg/day
1.3
-

Re-evaluate dosing.
Do not exceed 8 mg/day
20 mg/day
4 mg/day
1.6
-
40 mg/day
4 mg/day
1.8
-
Enzyme (CYP3A/ PgP inducers) Inducers
 
 
 
 
 
Carbamazepine
573 ± 168 mg/day
 
3 mg twice daily
 
0.51
 
0.55
 

Titrate dose upwards.
Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) inhibitors
 
 
 
 
 
Ranitidine
150 mg twice daily
1 mg single dose
1.2
1.4
Dose adjustment not needed
Cimetidine
400 mg twice daily
1 mg single dose
1.1
1.3
Dose adjustment not needed
Erythromycin
500 mg four times daily
1 mg single dose
1.1
0.94
Dose adjustment not needed
Other Drugs
 
 
 
 
 
Amitriptyline
50 mg twice daily
3 mg twice daily
1.2
1.1
Dose adjustment not Needed


Table name:
blood dyscrasias -
  see CONTRAINDICATIONS
cancer
collagen vascular disease
congestive heart failure
diarrhea
elevated temperature
hepatic disorders
  infectious hepatitis
  jaundice
hyperthyroidism
poor nutritional state
steatorrhea
vitamin K deficiency


Table name:
Interacting Drug Interaction
Theophylline Serious and fatal reactions. Avoid concomitant use. Monitor serum level ( 7)
Warfarin Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding ( 7)
Antidiabetic agents Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose ( 7)
Phenytoin Monitor phenytoin level ( 7)
Methotrexate Monitor for methotrexate toxicity ( 7)
Cyclosporine May increase serum creatinine. Monitor serum creatinine ( 7)
Multivalent cation-containing products including antacids, metal cations or didanosine Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin ( 7)


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 45.1, 7.1, 7.2, 7.3, 12.3)
   Interacting Agents    Prescribing Recommendations
   Strong CYP3A4 inhibitors (e.g.,Itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol
   Contraindicated with simvastatin
   Verapamil, diltiazem
   Do not exceed 10 mg simvastatin daily
   Amiodarone, amlodipine, ranolazine
   Do not exceed 20 mg simvastatin daily
   Grapefruit juice
   Avoid large quantities of grapefruit juice (>1 quart daily)


Table name:
Antibiotics Anticonvulsants Other Drugs/Dietary Supplements
nafcillin carbamazepine bosentan
rifampin oxcarbazepine octreotide
  phenobarbital orlistat
  phenytoin sulfinpyrazone
    St. John's Wort
    terbinafine
    ticlopidine


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
↓ =  Decreased (induces lamotrigine glucuronidation).
↑ =  Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
Concomitant Drug
Effect on Concentration of Lamotrigine or Concomitant Drug
Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and
150 mcg levonorgestrel
↓ lamotrigine
 
↓ levonorgestrel
Decreased lamotrigine concentrations approximately 50%.
Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide
↓ lamotrigine
 
 
 
? carbamazepine epoxide
Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
 
May increase carbamazepine epoxide levels.
Lopinavir/ritonavir
↓ lamotrigine
 
Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir
↓ lamotrigine
 
Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone
↓ lamotrigine
Decreased lamotrigine concentration approximately 40%.
Phenytoin
↓ lamotrigine
Decreased lamotrigine concentration approximately 40%.
Rifampin
↓ lamotrigine
Decreased lamotrigine AUC approximately 40%.
Valproate
↑ lamotrigine
 
 
? valproate
Increased lamotrigine concentrations slightly more than 2-fold.
 
There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( , , , ) 2.6 5.1 7 12.3
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Table 2 Steady-State Plasma Concentrations of Felbamate When Coadministered With Other AEDs
*Not administered but an active metabolite of carbamazepine.
**No significant effect.
AED
Coadministered
AED
Concentration
Felbamate
Concentration
Phenytoin
Valproate ↔**
Carbamazepine (CBZ)
*CBZ epoxide

Phenobarbital


Table name:
Interacting DrugInteracting Drug InteractionInteraction
Interacting Drug Interaction
 Multivalent cation-containing products including antacids, metal cations or didanosine
 Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products (2.4, 7.1)
 Warfarin
 Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
 Antidiabetic agents
 Carefully monitor blood glucose (5.12, 7.3)


Table name:
Table 2. Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T4 and T3 serum transport - but FT4 concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates (> 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T4 5'-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors
(SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 2: Drugs That Affect Phenytoin Concentrations 
* Antacids may affect absorption of phenytoin.
† The induction potency of St. John's wort may vary widely based on preparation. 
Interacting Agent
Examples
Drugs that may increase phenytoin serum levels
Antiepileptic drugs
Ethosuximide, felbamate, oxcarbazepine, methsuximide, topiramate
Azoles
Fluconazole, ketoconazole, itraconazole, miconazole, voriconazole
Antineoplastic agents
Capecitabine, fluorouracil
Antidepressants
Fluoxetine, fluvoxamine, sertraline
Gastric acid reducing agents
H2 antagonists (cimetidine), omeprazole
Sulfonamides
Sulfamethizole, sulfaphenazole, sulfadiazine, sulfamethoxazole-trimethoprim
Other
Acute alcohol intake, amiodarone, chloramphenicol, chlordiazepoxide, disulfiram, estrogen, fluvastatin, isoniazid, methylphenidate, phenothiazines, salicylates, ticlopidine, tolbutamide, trazodone, warfarin
Drugs that may decrease phenytoin serum levels
Antacids*
Calcium carbonate, aluminum hydroxide, magnesium hydroxide
Prevention or Management: Phenytoin and antacids should not be taken at the same time of day
Antineoplastic agents usually in combination
Bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate
Antiviral agents
Fosamprenavir, nelfinavir, ritonavir
Antiepileptic drugs
Carbamazepine, vigabatrin
Other
Chronic alcohol abuse, diazepam, diazoxide, folic acid, reserpine, rifampin, St. John's wort, sucralfate, theophylline
Drugs that may either increase or decrease phenytoin serum levels
Antiepileptic drugs
Phenobarbital, valproate sodium, valproic acid


Table name:
Interacting Agents Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone Avoid simvastatin
Gemfibrozil, cyclosporine, danazol Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil Do not exceed 20 mg simvastatin daily
Grapefruit juice Avoid large quantities of grapefruit juice (> 1 quart daily)


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on
Concentration of Lamotrigine or Concomitant Drug
Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine Decreased lamotrigine concentrations approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? carbamazepine epoxide May increase carbamazepine epoxide levels.
 Lopinavir/ritonavir ↓ lamotrigine Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir ↓ lamotrigine Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine
Increased lamotrigine concentrations slightly more than 2-fold.
? valproate There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.


Table name:
Table 18Summary of Effect of Coadministered Drugs on Exposure to Active Moiety(Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients withSchizophrenia
*Change relative to reference
Coadministered Drug
Dosing Schedule

Effect on Active
Moiety
(Risperidone + 9-
Hydroxy-
Risperidone (Ratio*)

Risperidone Dose
Recommendation

Coadministered Drug
Risperidone
AUC
Cm a x

Enzyme (CYP2D6) 
Inhibitors 





Fluoxetine 
20 mg/day
2 or 3 mg twice
daily
1.4
1.5
Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine 
10 mg/day
4 mg/day
1.3
-
Re-evaluate dosing. 

20 mg/day
4 mg/day
1.6
-
Do not exceed 8 mg/day

40 mg/day
4 mg/day
1.8
-

Enzyme (CYP3A/ 
PgP inducers) 





Carbamazepine 
573 ± 168 mg/day
3 mg twice daily
0.51
0.55
Titrate dose upwards.
Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) 
Inhibitors 





Ranitidine 
150 mg twice daily
1 mg single dose
1.2
1.4
Dose adjustment not
needed
Cimetidine 
400 mg twice daily
1 mg single dose
1.1
1.3
Dose adjustment not
needed
Erythromycin 
500 mg four times
daily
1 mg single dose
1.1
0.94
Dose adjustment not
needed
Other Drugs 





Amitriptyline 
50 mg twice daily
3 mg twice daily
1.2
1.1
Dose adjustment not
needed


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.11, 7.3)


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment
↓= Decreased (induces lamotrigine glucuronidation).
↑= Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine Decreased lamotrigine concentrations approximately 50%.
↓ levonorgestrel Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide ↓ lamotrigine Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? carbamazepine epoxide May increase carbamazepine epoxide levels.
Lopinavir/ritonavir ↓ lamotrigine Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir ↓ lamotrigine Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Phenytoin ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.
Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.
Valproate ↑ lamotrigine Increased lamotrigine concentrations slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.
? valproate


Table name:
Table 3Drugs that Can Increase the Risk of Bleeding
Drug  Class
Specific  Drugs
Anticoagulants 
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin 
Antiplatelet Agents 
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine 
Nonsteroidal Anti-Inflammatory Agents 
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac 
Serotonin Reuptake Inhibitors 
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone 


Table name:
Drugs that Affect Renal Function A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDS], COX-2 inhibitors may impair the excretion of digoxin.
Antiarrthymics Dofetilide Concomitant administration with digoxin was associated with a higher rate of torsades de pointes
Sotalol Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
Dronedarone Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone Analog Teriparatide Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement Thyroid Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics Epinephrine
Norepinephrine     
Dopamine
Can increase the risk of cardiac arrhythmias
Neuromuscular Blocking Agents      Succinylcholine May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.
Supplements Calcium If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.


Table name:
Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme
Inhibitors
Inducers
CYP2C9 
amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast
aprepitant, bosentan, carbamazepine, phenobarbital, rifampin 
CYP1A2 
acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton
montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking 
CYP3A4 
alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton
armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide 


Table name:
Table 4 Established and Other Potentially SignificantThis table is not all inclusive. Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction
Concomitant Drug Class: Drug Name Effect on ConcentrationIncrease=↑; Decrease=↓; No Effect=↔ Clinical Comment
Antacids:
  antacids (e.g., aluminium, magnesium hydroxide, or calcium carbonate)
↔ rilpivirine (antacids taken at least 2 hours before or at least 4 hours after rilpivirine)
↓ rilpivirine (concomitant intake)
The combination of COMPLERA and antacids should be used with caution as coadministration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). Antacids should only be administered either at least 2 hours before or at least 4 hours after COMPLERA.
Antimycobacterials:
  rifabutin
↓ rilpivirineThe interaction was evaluated in a clinical study. All other drug-drug interactions shown are predicted. Concomitant use of COMPLERA with rifabutin may cause significant decreases in rilpivirine plasma concentrations (induction of CYP3A enzymes). If COMPLERA is coadministered with rifabutin, an additional 25 mg tablet of rilpivirine (Edurant) once per day is recommended to be taken concomitantly with COMPLERA and with a meal for the duration of rifabutin coadministration.
Azole Antifungal Agents:
  fluconazole
  itraconazole
  ketoconazole
  posaconazole
  voriconazole
↑ rilpivirine , This interaction study has been performed with a dose higher than the recommended dose for rilpivirine. The dosing recommendation is applicable to the recommended dose of rilpivirine 25 mg once daily.
↓ ketoconazole ,
Concomitant use of COMPLERA with azole antifungal agents may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). No dose adjustment is required when COMPLERA is coadministered with azole antifungal agents. Clinically monitor for breakthrough fungal infections when azole antifungals are coadministered with COMPLERA.
Hepatitis C Antiviral Agents:
  ledipasvir/sofosbuvir
  sofosbuvir/velpatasvir
↑ tenofovir Patients receiving COMPLERA concomitantly with HARVONI® (ledipasvir/sofosbuvir) or EPCLUSA® (sofosbuvir/velpatasvir) should be monitored for adverse reactions associated with tenofovir DF.
H2-Receptor Antagonists:
  cimetidine
  famotidine
  nizatidine
  ranitidine
↔ rilpivirine , (famotidine taken 12 hours before rilpivirine or 4 hours after rilpivirine)
↓ rilpivirine , (famotidine taken 2 hours before rilpivirine)
The combination of COMPLERA and H2-receptor antagonists should be used with caution as coadministration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). H2-receptor antagonists should only be administered at least 12 hours before or at least 4 hours after COMPLERA.
Macrolide or Ketolide Antibiotics:
  clarithromycin
  erythromycin
  telithromycin
↑ rilpivirine
↔ clarithromycin
↔ erythromycin
↔ telithromycin
Concomitant use of COMPLERA with clarithromycin, erythromycin, or telithromycin may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). Where possible, alternatives such as azithromycin should be considered.
Narcotic Analgesics:
  methadone
↓ R(–) methadone
↓ S(+) methadone
↔ rilpivirine
↔ methadone (when used with tenofovir)
No dose adjustments are required when initiating coadministration of methadone with COMPLERA. However, clinical monitoring is recommended as methadone maintenance therapy may need to be adjusted in some patients.


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may
result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-
   containing radiographic
   contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which
may result in hyperthyroidism
Amiodarone
Iodide (including iodine-
containing Radiographic
contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase Drugs that may decrease
serum TBG concentration serum TBG concentration
Clofibrate Androgens / Anabolic Steroids
Estrogen-containing oral Asparaginase
   contraceptives Glucocorticoids
Estrogens (oral) Slow-Release Nicotinic Acid
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal
Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake
Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
NITROPRUSSIDE
Para-aminosalicylate sodium
Perphenazine
Resorcinol
 (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name: Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.During concomitant use of diclofenac potassium tablets and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of diclofenac potassium tablets and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS: Renal Toxicity and Hyperkalemia ). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Table 2. Clinically Significant Drug Interactions with Diclofenac
Drugs That Interfere with Hemostasis
Clinical Impact:
Intervention: Monitor patients with concomitant use of diclofenac potassium tablets with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS: Hematological Toxicity ).
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation ).
Intervention: Concomitant use of diclofenac potassium tablets and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS: Hematological Toxicity ). Diclofenac potassium tablets are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:
 
Intervention:
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of diclofenac potassium tablets with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS: Renal Toxicity and Hyperkalemia ).
Digoxin
Clinical Impact: The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of diclofenac potassium tablets and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of diclofenac potassium tablets and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of diclofenac potassium tablets and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of diclofenac potassium tablets and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of diclofenac potassium tablets and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation ).
Intervention: The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of diclofenac potassium tablets and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of diclofenac potassium tablets and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
CYP2C9 Inhibitors or Inducers:
Clinical Impact: Diclofenac is metabolized by cytochrome P450 enzymes, predominantly by CYP2C9. Co-administration of diclofenac with CYP2C9 inhibitors (e.g. voriconazole) may enhance the exposure and toxicity of diclofenac whereas coadministration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of diclofenac.
Intervention: A dosage adjustment may be warranted when diclofenac is administered with CYP2C9 inhibitors or inducers (see CLINICAL PHARMACOLOGY: Pharmacokinetics ).


Table name:
 Interacting Drug  Interaction
 Multivalent cation-containing products including antacids, metal cations or didanosine  Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
 Warfarin  Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
 Antidiabetic agents  Carefully monitor blood glucose (5.11, 7.3)


Table name:
Concomitant Drug Name or Drug Class
Clinical Rationale
Clinical Recommendation

StrongCYP3A4Inhibitors (e.g.,itraconazole,clarithromycin) or strongCYP2D6inhibitors (e.g.,quinidine,fluoxetine,paroxetine) 
The concomitant use of aripiprazole tablets withstrong CYP3A4 orCYP2D6inhibitorsincreasedthe exposure ofaripiprazole tabletscomparedto the use of aripiprazole tabletsalone[seeCLINICALPHARMACOLOGY(12.3)].
Withconcomitant use of aripiprazole tablets with a strongCYP3A4inhibitororCYP2D6inhibitor, reducethearipiprazole tablets dosage[see DOSAGEANDADMINISTRATION(2.7)].
StrongCYP3A4Inducers (e.g.,carbamazepine,rifampin)
The concomitant use of aripiprazole tabletsandcarbamazepine decreased the exposure of aripiprazole tablets compared to the use of aripiprazole tablets alone [see CLINICALPHARMACOLOGY(12.3)].
Withconcomitant use of aripiprazole tablets with a strongCYP3A4inducer, consider increasing the aripiprazole tabletsdosage[see DOSAGE ANDADMINISTRATIO(2.7)].
AntihypertensiveDrugs
Duetoitsalphaadrenergicantagonism,aripiprazole tablets hasthepotentialtoenhance the effect of certainantihypertensive agents.
Monitor bloodpressureand adjustdoseaccordingly[seeWARNINGS AND PRECAUTIONS(5.7)].
Benzodiazepines(e.g., lorazepam)
Theintensityofsedationwas greaterwith the combination of oral aripiprazole tabletsandlorazepam as comparedtothat observedwith aripiprazole alone.Theorthostatichypotension observed wasgreaterwith the combination as comparedtothatobserved withlorazepamalone[seeWARNINGSANDPRECAUTIONS(5.7)]
Monitorsedation and blood pressure.Adjust dose accordingly.


Table name:
Interacting Drug Interaction
Theophylline Serious and fatal reactions. Avoid concomitant use. Monitor serum level. (5.9, 7)
Warfarin Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding. (7)
Antidiabetic agents Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose. (7)
Phenytoin Monitor phenytoin level. (7)
Methotrexate Monitor for methotrexate toxicity. (7)
Cyclosporine May increase serum creatinine. Monitor serum creatinine. (7)
Multivalent cation-containing products including antacids, metal cations or didanosine Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin. (2.2, 7)


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
 Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration  Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
 Drugs that may alter T 4 and T 3 metabolism
 Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Drugs that Affect Renal Function A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDS], COX-2 inhibitors may impair the excretion of digoxin.
Antiarrthymics Dofetilide Concomitant administration with digoxin was associated with a higher rate of torsades de pointes
Sotalol Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
Dronedarone Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone Analog Teriparatide Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement Thyroid Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics Epinephrine
Norepinephrine     
Dopamine
Can increase the risk of cardiac arrhythmias
Neuromuscular Blocking Agents      Succinylcholine May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.
Supplements Calcium If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.


Table name:
Table 13. Established and Other Potentially Significant Drug Interactions
↓ =  Decreased (induces lamotrigine glucuronidation).
↑ =  Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
Concomitant Drug
Effect on Concentration of Lamotrigine or Concomitant Drug
Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and
150 mcg levonorgestrel
↓ lamotrigine
 
↓ levonorgestrel
Decreased lamotrigine concentrations approximately 50%.
Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide
↓ lamotrigine
 
 
 
? carbamazepine epoxide
Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
 
May increase carbamazepine epoxide levels.
Lopinavir/ritonavir
↓ lamotrigine
 
Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir
↓ lamotrigine
 
Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone
↓ lamotrigine
Decreased lamotrigine concentration approximately 40%.
Phenytoin
↓ lamotrigine
Decreased lamotrigine concentration approximately 40%.
Rifampin
↓ lamotrigine
Decreased lamotrigine AUC approximately 40%.
Valproate
↑ lamotrigine
 
 
? valproate
Increased lamotrigine concentrations slightly more than 2-fold.
 
There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.


Table name:
Table 9. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class:
Drug Name
Effect on Concentration of Lopinavir or Concomitant Drug Clinical Comment
*   see Clinical Pharmacology (12.3) for Magnitude of Interaction.
HIV-1 Antiviral Agents
Non-nucleoside Reverse Transcriptase Inhibitors:
efavirenz*,
nevirapine*
↓ lopinavir KALETRA dose increase is recommended in all patients [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
Increasing the dose of KALETRA tablets to 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) twice daily co-administered with efavirenz resulted in similar lopinavir concentrations compared to KALETRA tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz.
Increasing the dose of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice daily co-administered with efavirenz resulted in significantly higher lopinavir plasma concentrations compared to KALETRA tablets 400/100 mg twice daily without efavirenz.
KALETRA should not be administered once daily in combination with efavirenz or nevirapine
[see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
Non-nucleoside Reverse Transcriptase Inhibitor:
delavirdine
↑ lopinavir Appropriate doses of the combination with respect to safety and efficacy have not been established.
Nucleoside Reverse Transcriptase Inhibitor:
didanosine
KALETRA tablets can be administered simultaneously with didanosine without food.
For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food).
Nucleoside Reverse Transcriptase Inhibitor:
tenofovir
↑ tenofovir KALETRA increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir.
Nucleoside Reverse Transcriptase Inhibitor:
abacavir
zidovudine
↓ abacavir
↓ zidovudine
KALETRA induces glucuronidation; therefore, KALETRA has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown.
HIV-1 Protease Inhibitor:
amprenavir*
↑ amprenavir
↓ lopinavir
KALETRA should not be administered once daily in combination with amprenavir
[see Dosage and Administration (2.1)].
HIV-1 Protease Inhibitor:
fosamprenavir/ritonavir
↓ amprenavir
↓ lopinavir
An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor:
indinavir*
↑ indinavir Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily [see Clinical Pharmacology (12.3)]. KALETRA once daily has not been studied in combination with indinavir.
HIV-1 Protease Inhibitor:
nelfinavir*
↑ nelfinavir
↑ M8 metabolite of nelfinavir
↓ lopinavir
KALETRA should not be administered once daily in combination with nelfinavir
[see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].

HIV-1 Protease Inhibitor:
ritonavir*
↑ lopinavir Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor:
saquinavir*
↑ saquinavir The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily.
KALETRA once daily has not been studied in combination with saquinavir.
HIV-1 Protease Inhibitor:
tipranavir
↓ lopinavir AUC and Cmin KALETRA should not be administered with tipranavir (500 mg twice daily) co-administered with ritonavir (200 mg twice daily).
HIV CCR5 – antagonist: maraviroc ↑ maraviroc Concurrent administration of maraviroc with KALETRA will increase plasma levels of maraviroc. When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for Selzentry® (maraviroc).
Other Agents
Antiarrhythmics:
amiodarone,
bepridil,
lidocaine (systemic), and
quinidine
↑ antiarrhythmics Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA.
Anticancer Agents:
vincristine,
vinblastine,
dasatinib,
nilotinib
↑ anticancer agents Concentrations of these drugs may be increased when co-administered with KALETRA resulting in the potential for increased adverse events usually associated with these anticancer agents.
For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when KALETRA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor.
A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as KALETRA. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions.
Anticoagulant:
warfarin
Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants:
carbamazepine,
phenobarbital,
phenytoin
↓ lopinavir
↓ phenytoin
KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution.
KALETRA should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin.

In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA.
Antidepressant:
bupropion
↓ bupropion
↓ active metabolite,
hydroxybupropion
Concurrent administration of bupropion with KALETRA may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion.
Antidepressant:
trazodone
↑ trazodone Concomitant use of trazodone and KALETRA may increase concentrations of trazodone. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered.
Anti-infective:
clarithromycin
↑ clarithromycin For patients with renal impairment, the following dosage adjustments should be considered: For patients with CLCR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients with CLCR < 30 mL/min the dose of clarithromycin should be decreased by 75%.
No dose adjustment for patients with normal renal function is necessary.
Antifungals:
ketoconazole*,
itraconazole,
voriconazole
↑ ketoconazole
↑ itraconazole
↓ voriconazole
High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended.
Co-administration of voriconazole with KALETRA has not been studied. However, a study has been shown that administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%; therefore, co-administration of KALETRA and voriconazole may result in decreased voriconazole concentrations and the potential for decreased voriconazole effectiveness and should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Otherwise, alternative antifungal therapies should be considered in these patients.
Anti-gout:
colchicine
↑ colchicine Patients with renal or hepatic impairment should not be given colchicine with KALETRA.
Treatment of gout flares-co-administration of colchicine in patients on KALETRA:
0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days.
Prophylaxis of gout flares-co-administration of colchicine in patients on KALETRA:
If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.
If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.
Treatment of familial Mediterranean fever (FMF)-co-administration of colchicine in patients on KALETRA:
Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Antimycobacterial:
rifabutin*
↑ rifabutin and rifabutin metabolite Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary.
Antimycobacterial:
rifampin
↓ lopinavir May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents. A study evaluated combination of rifampin 600 mg once daily, with KALETRA 800/200 mg twice daily or KALETRA 400/100 mg + ritonavir 300 mg twice daily. Pharmacokinetic and safety results from this study do not allow for a dose recommendation. Nine subjects (28%) experienced a ≥ grade 2 increase in ALT/AST, of which seven (21%) prematurely discontinued study per protocol. Based on the study design, it is not possible to determine whether the frequency or magnitude of the ALT/AST elevations observed is higher than what would be seen with rifampin alone [see Clinical Pharmacology (12.3) for magnitude of interaction].
Antiparasitic:
atovaquone
↓ atovaquone Clinical significance is unknown; however, increase in atovaquone doses may be needed.
Benzodiazepines: parenterally administered midazolam ↑ midazolam Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, KALETRA should not be given with orally administered midazolam [see Contraindications (4)]. If KALETRA is coadministered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.
Calcium Channel Blockers, dihydropyridine:
e.g., felodipine,
nifedipine,
nicardipine
↑ dihydropyridine calcium channel blockers Caution is warranted and clinical monitoring of patients is recommended.
Contraceptive:
ethinyl estradiol*
↓ ethinyl estradiol Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended.
Corticosteroid:
dexamethasone

↓ lopinavir Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly.


disulfiram/metronidazole KALETRA oral solution contains alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).
Endothelin receptor antagonists:
bosentan
↑ bosentan Co-administration of bosentan in patients on KALETRA:
In patients who have been receiving KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Co-administration of KALETRA in patients on bosentan:
Discontinue use of bosentan at least 36 hours prior to initiation of KALETRA.
After at least 10 days following the initiation of KALETRA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
HMG-CoA Reductase Inhibitors:
atorvastatin
rosuvastatin
↑ atorvastatin
↑ rosuvastatin
Use lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin or fluvastatin in combination with KALETRA.
Immunosuppressants:
cyclosporine,
tacrolimus,
rapamycin
↑ immunosuppressants Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA.
Inhaled Steroid:
fluticasone
↑ fluticasone Concomitant use of fluticasone propionate and KALETRA may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during post-marketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Co-administration of fluticasone propionate and KALETRA is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effect.
Long-acting beta-adrenoceptor agonist:
salmeterol
↑ salmeterol Concurrent administration of salmeterol and KALETRA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Narcotic Analgesic:
methadone*
fentanyl
↓ methadone
↑ fentanyl
Dosage of methadone may need to be increased when co-administered with KALETRA.
Concentrations of fentanyl are expected to increase. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with KALETRA.
PDE5 inhibitors:
sildenafil,
tadalafil,
vardenafil
↑ sildenafil
↑ tadalafil
↑ vardenafil
Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs is expected to substantially increase their concentrations and may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection.
Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH):
Sildenafil (Revatio®) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with KALETRA [see Contraindications (4)].
The following dose adjustments are recommended for use of tadalafil (Adcirca®) with KALETRA:
Co-administration of ADCIRCA in patients on KALETRA:
In patients receiving KALETRA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.
Co-administration of KALETRA in patients on ADCIRCA:
Avoid use of ADCIRCA during the initiation of KALETRA. Stop ADCIRCA at least 24 hours prior to starting KALETRA. After at least one week following the initiation of KALETRA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.
Use of PDE5 inhibitors for erectile dysfunction:

It is recommended not to exceed the following doses: Sildenafil: 25 mg every 48 hours Tadalafil: 10 mg every 72 hours Vardenafil: 2.5 mg every 72 hours Use with increased monitoring for adverse events.


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
 Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration  Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
 Drugs that may alter T 4 and T 3 metabolism
 Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Drugs that Affect Renal Function
A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDS], COX-2 inhibitors may impair the excretion of digoxin.
Antiarrthymics
Dofetilide
Concomitant administration with digoxin was associated with  a higher rate of torsades de pointes
Sotalol
Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
Dronedarone
Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone Analog
Teriparatide
Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement
Thyroid Supplement
Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics
Epinephrine
Norepinephrine
Dopamine
Can increase the risk of cardiac arrhythmias
Neuromuscular Blocking Agents
Succinylcholine
May cause sudden extrusion of potassium from muscle cells causing arrhythmias inpatients taking digoxin.
Supplements
Calcium
If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.
Hyperpolarization-activated cyclic nucleotide-gated channel blocker  Ivabradine Can increase the risk of bradycardia.


Table name:
Table 7 Summary of AED Interactions with Oxcarbazepine
AED Coadministered Dose of AED (mg/day) Oxcarbazepine Dose (mg/day) Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval) Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine 400-2000 900 nc1 40% decrease
[CI: 17% decrease,
57% decrease]
Phenobarbital 100-150 600-1800 14% increase
[CI: 2% increase,
24% increase]
25% decrease
[CI: 12% decrease,
51% decrease]
Phenytoin 250-500 600-1800
>1200-2400
nc1,2
up to 40%
increase3 
[CI: 12% increase,
60% increase]
30% decrease
[CI: 3% decrease,
48% decrease]
Valproic acid 400-2800 600-1800 nc1 18% decrease
[CI: 13% decrease,
40% decrease]


Table name:
Table 5: Effects on Steady-State Fexofenadine Pharmacokinetics After 7 Days of Coadministration With Fexofenadine Hydrochloride 120 mg Every 12 Hours in Healthy Adult Subjects (n = 24)
Concomitant Drug CmaxSS (Peak plasma concentration) AUCss(0-12h) (Extent of systemic exposure)
Erythromycin (500 mg every 8 hrs) +82% +109%
Ketoconazole (400 mg once daily) +135% +164%


Table name:
AED Co-administered AED Concentration Topiramate Concentration
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated
Phenytoin NC or 25% increase = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. 48% decrease
Carbamazepine (CBZ) NC 40% decrease
CBZ epoxide = Is not administered but is an active metabolite of carbamazepine. NC NE
Valproic acid 11% decrease 14% decrease
Phenobarbital NC NE
Primidone NC NE
Lamotrigine NC at TPM doses up to 400 mg/day 13% decrease


Table name:
Table 6: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies [see Clinical Pharmacology (12.3) ( Tables 12 and 13) for magnitude of interaction]
Concomitant Drug Class:
Drug Name
Effect on
Concentration
Clinical Comment
HIV Antiviral Agents: Reverse Transcriptase Inhibitors
Delavirdine ↑ nelfinavir (C min)
↓ delavirdine
Concentrations of nelfinavir were increased while concentrations of delavirdine were decreased when the two agents were coadministered. Appropriate doses of the combination, with respect to safety and efficacy, have not been established.
Nevirapine ↓ nelfinavir (C min) Concentrations of nelfinavir were decreased when coadministered with nevirapine. An appropriate dose of nelfinavir with respect to safety and efficacy has not been established.
Didanosine ↔ nelfinavir There was no change in nelfinavir concentration when coadministered with didanosine. However, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after VIRACEPT (given with food).
HIV Antiviral Agents: Protease Inhibitors
Indinavir ↑ nelfinavir
↑ indinavir
Concentrations of both indinavir and nelfinavir were increased when the two agents were coadministered. Appropriate doses for these combinations, with respect to safety and efficacy, have not been established.
Ritonavir ↑ nelfinavir
↔ ritonavir
Concentrations of nelfinavir were increased when coadministered with ritonavir. An appropriate dose of nelfinavir for this combination, with respect to safety and efficacy, has not been established.
Saquinavir ↑ nelfinavir
↑ saquinavir
Concentrations of both saquinavir and nelfinavir were increased when the two agents were coadministered. Appropriate doses for these combinations, with respect to safety and efficacy, have not been established.
ANTICOAGULANT
Warfarin Warfarin Coadministration of warfarin and VIRACEPT may affect concentrations of warfarin. It is recommended that the INR (international normalized ratio) be monitored carefully during treatment with VIRACEPT, especially when commencing therapy.
ANTICONVULSANTS
Carbamazepine Phenobarbital
Phenytoin

↓ nelfinavir

↓ phenytoin
Concentrations of nelfinavir may be decreased. VIRACEPT may not be effective due to decreased nelfinavir plasma concentrations in patients taking these agents concomitantly.
Phenytoin plasma/serum concentrations should be monitored; phenytoin dose may require adjustment to compensate for altered phenytoin concentration.
ANTIDEPRESSANT
Trazodone ↑ trazodone Concomitant use of trazodone and VIRACEPT may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as VIRACEPT, the combination should be used with caution and a lower dose of trazodone should be considered.
ANTIGOUT
Colchicine ↑ colchicines Patients with renal or hepatic impairment should not be given colchicine with VIRACEPT due to the risk of colchicine toxicity.

Treatment of gout flares –
co- administration of colchicine in patients on VIRACEPT:

0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days.

Prophylaxis of gout-flares –
coadministration of colchicine in patients on VIRACEPT:


If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.
If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.

Treatment of familial Mediterranean fever (FMF)– coadministration of colchicine in patients on VIRACEPT:

Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
ANTIMYCOBACTERIAL
Rifabutin ↑ rifabutin
↓ nelfinavir
  (750 mg TID)
↔ nelfinavir
  (1250 mg BID)
It is recommended that the dose of rifabutin be reduced to one-half the usual dose when administered with VIRACEPT; 1250 mg BID is the preferred dose of VIRACEPT when coadministered with rifabutin.
ENDOTHELIN RECEPTOR ANTAGONIST
Bosentan ↑ bosentan Concentrations of bosentan may be increased when coadministered with VIRACEPT. Coadministration of bosentan in patients on VIRACEPT or coadministration of VIRACEPT in patients on bosentan:
Start at or adjust bosentan to 62.5 mg once daily or every other day based upon individual tolerability.
HMG-CoA REDUCTASE INHIBITORS
Atorvastatin
Rosuvastatin
↑ atorvastatin
↑ rosuvastatin
Titrate atorvastatin dose carefully and use the lowest necessary dose; do not exceed atorvastatin 40 mg/day.
IMMUNOSUPPRESSANTS
Cyclosporine
Tacrolimus
Sirolimus
↑ immuno-suppressants
↑ nelfinavir
Concentrations of these immunosuppressants and nelfinavir may be increased by coadministration of these agents with nelfinavir.
INHALED BETA AGONIST
Salmeterol ↑ salmeterol Concurrent administration of salmeterol with VIRACEPT is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
INHALED/NASAL STEROID
Fluticasone ↑ fluticasone Concomitant use of fluticasone propionate and VIRACEPT may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use.
MACROLIDE ANTIBIOTIC
Azithromycin ↑ azithromycin Dose adjustment of azithromycin is not recommended, but close monitoring for known side effects such as liver enzyme abnormalities and hearing impairment is warranted.
NARCOTIC ANALGESIC
Methadone ↓ methadone Concentrations of methadone were decreased when coadministered with VIRACEPT. Dosage of methadone may need to be increased when coadministered with VIRACEPT.
HORMONAL CONTRACEPTIVES
Ethinyl estradiol
Norethindrone
↓ ethinyl estradiol
↓ norethindrone
Concentrations of ethinyl estradiol and norethindrone were decreased when coadministered with VIRACEPT. Alternative or additional contraceptive measures should be used when oral contraceptives containing ethinyl estradiol or norethindrone and VIRACEPT are coadministered.
PDE5 INHIBITORS
Sildenafil
Vardenafil
Tadalafil
↑ PDE5 Inhibitors Concomitant use of PDE5 inhibitors and VIRACEPT should be undertaken with caution.

May result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism.

Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH):

• Use of sildenafil (REVATIO) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) [see Contraindications (4)] .

• The following dose adjustments are recommended for use of tadalafil (ADCIRCA™) with VIRACEPT:

Coadministration of ADCIRCA in patients on VIRACEPT or coadministration of VIRACEPT in patients on ADCIRCA:

Start at or adjust ADCIRCA to 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Use of PDE5 inhibitors for erectile dysfunction:

Sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg in 24 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours, is recommended. Use with increased monitoring for adverse events.
PROTON PUMP INHIBITORS
Omeprazole ↓ nelfinavir Omeprazole decreases the plasma concentrations of nelfinavir. Concomitant use of proton pump inhibitors and VIRACEPT may lead to a loss of virologic response and development of resistance.
ANTIPSYCHOTICS
Quetiapine ↑ quetiapine Initiation of VIRACEPT in patients taking quetiapine:
Consider alternative antiretroviral therapy to avoid increases in quetiapine drug exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring.
Initiation of quetiapine in patients taking VIRACEPT:
Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.


Table name:
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily


Table name:
Classes of Drugs
Adrenal Cortical Steroid
  Inhibitors
Antacids
Antianxiety Agents
Antiarrhythmics†
Antibiotics†
Anticonvulsants†
Antidepressants†
Antihistamines
Antineoplastics†
Antipsychotic Medications
Antithyroid Drugs†
Barbiturates
Diuretics†
Enteral Nutritional
  Supplements
Fungal Medications, Systemic†
Gastric Acidity and Peptic
  Ulcer Agents†
Hypnotics†
Hypolipidemics†
  Bile Acid-Binding Resins†
  HMG-CoA Reductase Inhibitors†
Immunosuppressives
Oral Contraceptives, Estrogen
  Containing
Selective Estrogen Receptor
  Modulators
Steroids, Adrenocortical†
Tuberculosis Agents†
Vitamins†


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
 Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration  Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
 Drugs that may alter T 4 and T 3 metabolism
 Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
Table 6. Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology (12.3)]
Drug/Drug Class
(Mechanism of Interaction by the Drug)
Voriconazole Plasma Exposure
(Cmax and AUCτ after 200 mg q12h)
Recommendations for Voriconazole Dosage Adjustment/Comments
Rifampin* and Rifabutin*
(CYP450 Induction)
Significantly Reduced Contraindicated
Efavirenz (400 mg q 24h)** (CYP450 Induction) Efavirenz (300 mg q 24h) ** (CYP450 Induction) Significantly Reduced Slight decrease in AUCt Contraindicated When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)** (CYP450 Induction) Significantly Reduced Contraindicated
Low-dose Ritonavir (100 mg q12h)** (CYP450 Induction) Reduced Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Carbamazepine
(CYP450 Induction)
Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction Contraindicated
Long Acting Barbiturates
(CYP450 Induction)
Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction Contraindicated
Phenytoin*
(CYP450 Induction)
Significantly Reduced Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg)
St. John’s Wort
(CYP450 inducer; P-gp inducer)
Significantly Reduced Contraindicated
Oral Contraceptives**
containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)
Increased Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole** (CYP2C9, CYP2C19 and CYP3A4 Inhibition) Significantly Increased Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole.
Other HIV Protease Inhibitors
(CYP3A4 Inhibition)
In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure
In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)
No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIs*** (CYP3A4 Inhibition or CYP450 Induction) In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to voriconazole
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure) Careful assessment of voriconazole effectiveness


Table name:
Drug Interactions Associated with Increased Risk of  Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice Avoid grapefruit juice


Table name:
Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
Interacting DrugInteracting Drug InteractionInteraction
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products (2.4, 7.1)
Warfarin
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents
Carefully monitor blood glucose (5.12, 7.3)


Table name:
Table 3: Summary of AED Interactions with Oxcarbazepine
 AED
Coadministered
 Dose of AED
(mg/day)
 Oxcarbazepine
Dose

(mg/day)
 Influence of
Oxcarbazepine on AED

Concentration

(Mean Change,

90% Confidence

Interval)
 Influence of
AED on MHD

Concentration

(Mean Change,

90% Confidence

Interval)
 Carbamazepine  400 to 2000  900  nc1  40% decrease
[CI: 17% decrease,
57% decrease]
 Phenobarbital  100 to 150  600 to 1800  14% increase
[CI: 2% increase,
24% increase]
 25% decrease
[CI: 12% decrease,
51% decrease]
 Phenytoin  250 to 500  600 to 1800
>1200 to 2400
 nc1,2
up to 40%
increase3 
[CI: 12% increase,
60% increase]
 30% decrease
[CI: 3% decrease,
48% decrease]
 Valproic acid  400 to 2800  600 to 1800  nc1  18% decrease
[CI: 13% decrease,
40% decrease]


Table name:
NA - Not available/reported
Digoxin concentrations increased > 50%
Digoxin Serum
Concentration Increase
Digoxin
AUC Increase
Recommendations
Amiodarone 70% NA Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin dose by approximately 30% to 50% and continue monitoring.
Captopril 58% 39%
Nitrendipine 57% 15%
Propafenone 35-85% NA
Quinidine 100% NA
Ranolazine 87% 88%
Ritonavir NA 86%
Verapamil 50-75% NA
Digoxin concentrations increased < 50%
Carvedilol 16% 14% Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin dose by approximately 15% to 30% and continue monitoring.
Diltiazem 20% NA
Nifedipine 45% NA
Rabeprazole 29% 19%
Telmisartan 20% NA
Digoxin concentrations increased, but magnitude is unclear
Alprazolam, Azithromycin, Clarithromycin, Cyclosporine, Diclofenac, Diphenoxylate, Epoprostenol, Erythromycin, Esomeprazole, Indomethacin, Itraconazole, Ketoconazole, Lansoprazole, Metformin, Omeprazole, Propantheline, Spironolactone, Tetracycline Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin concentrations decreased
Acarbose, Activated Charcoal, Albuterol, Antacids, Anticancer drugs, Cholestyramine, Colestipol, Exenatide, Kaolin-pectin, Meals High in Bran, Metoclpramide, Miglitol, Neomycin, Rifampin, Salbutamol, St.John's Wort, Sucralfate, Sulfasalazine Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20% to 40% as necessary.
No significant Digoxin concentration changes
Please refer to section 12.3 for a complete list of drugs which were studied but reported no significant changes on digoxin exposure. No additional actions are required.


Table name:
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may
result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-
   containing radiographic
   contrast agents)
Lithium
Methimazole
Propylthioracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which
may result in hyperthyroidism
Amiodarone
Iodide (including iodine-
containing Radiographic
contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T 4 absorption, which may result in hypothyroidism
Antacids
- Aluminum & Magnesium
Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Orlistat
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase Drugs that may decrease
serum TBG concentration serum TBG concentration
Clofibrate Androgens / Anabolic Steroids
Estrogen-containing oral Asparaginase
   contraceptives Glucocorticoids
Estrogens (oral) Slow-Release Nicotinic Acid
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal
Anti-lnflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T 4 5' - deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
-(e.g., Dexamethasone ≥ 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake
Inhibitors (SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines
- Interferon-α
- Interleukin-2
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
NITROPRUSSIDE
Para-aminosalicylate sodium
Perphenazine
Resorcinol
 (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.


Table name:
 Drugs That Interfere with Hemostasis
Clinical Impact:  •  Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of Celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.
•  Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
 Intervention:  Monitor patients with concomitant use of celecoxib with anticoagulants (e.g., warfarin), antiplatelet agents(e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptakeinhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
 Aspirin
 Clinical Impact:  Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin doesnot produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitantuse of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactionsas compared to use of the NSAID alone [see Warnings and Precautions (5.2)].
 In two studies in healthy volunteers, and in patients with osteoarthritis and established heart diseaserespectively, celecoxib (200 to 400 mg daily) has demonstrated a lack of interference with the cardioprotectiveantiplatelet effect of aspirin (100 to 325 mg).
 Intervention:  Concomitant use of celecoxib and analgesic doses of aspirin is not generally recommended because of theincreased risk of bleeding [see Warnings and Precautions (5.11)].
Celecoxib is not a substitute for low dose aspirin for cardiovascular protection.
 ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
 Clinical Impact:  •  NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).
•  In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
 Intervention:  •  During concomitant use of celecoxib and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.
•  During concomitant use of celecoxib and ACE-inhibitors or ARBs in patients who are elderly, volume- depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)].
•  When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
 Diuretics
 Clinical Impact:  Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect ofloop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to theNSAID inhibition of renal prostaglandin synthesis.
 Intervention:  During concomitant use of celecoxib with diuretics, observe patients for signs of worsening renal function,in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions(5.6)].
 Digoxin
 Clinical Impact:  The concomitant use of Celecoxib with digoxin has been reported to increase the serum concentration andprolong the half-life of digoxin.
 Intervention:  During concomitant use of celecoxib and digoxin, monitor serum digoxin levels.
 Lithium
 Clinical Impact:  NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. Themean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:  During concomitant use of celecoxib and lithium, monitor patients for signs of lithium toxicity.
 Methotrexate
 Clinical Impact:  Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g.,neutropenia, thrombocytopenia, renal dysfunction).
 Celecoxib has no effect on methotrexate pharmacokinetics.
 Intervention:  During concomitant use of celecoxib and methotrexate, monitor patients for methotrexate toxicity.
 Cyclosporine
 Clinical Impact:  Concomitant use of celecoxib and cyclosporine may increase cyclosporine’s nephrotoxicity.
 Intervention:  During concomitant use of celecoxib and cyclosporine, monitor patients for signs of worsening renalfunction.
 NSAIDs and Salicylates
 Clinical Impact:  Concomitant use of Celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk ofGI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
 Intervention:  The concomitant use of Celecoxib with other NSAIDs or salicylates is not recommended.
 Pemetrexed
 Clinical Impact:  Concomitant use of celecoxib and pemetrexed may increase the risk of pemetrexed-associatedmyelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
 Intervention:  During concomitant use of celecoxib and pemetrexed, in patients with renal impairment whose creatinineclearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of twodays before, the day of, and two days following administration of pemetrexed. 
In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives(e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five daysbefore, the day of, and two days following pemetrexed administration.
 CYP2C9 Inhibitors or inducers
  Clinical Impact:  Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Co­administration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may enhancethe exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g. rifampin)may lead to compromised efficacy of celecoxib.
 Intervention:  Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosageadjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers. [see Clinical Pharmacology (12.3)].
 CYP2D6 substrates
 Clinical Impact:  In vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore,there is a potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6 (e.g.atomoxetine), and celecoxib may enhance the exposure and toxicity of these drugs.
  Intervention:  Evaluate each patient’s medical history when consideration is given to prescribing celecoxib. A dosageadjustment may be warranted when celecoxib is administered with CYP2D6 substrates. [see Clinical Pharmacology (12.3)].
 Corticosteroids
 Clinical Impact:  Concomitant use of corticosteroids with celecoxib may increase the risk of GI ulceration or bleeding.
 Intervention:  Monitor patients with concomitant use of celecoxib with corticosteroids for signs of bleeding [seeWarnings and Precautions (5.2)].


Table name:
Table 3:   Drugs that Can Increase the Risk of Bleeding
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone


Table name:
Drug Interactions Associated with Increased Risk of  Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice Avoid grapefruit juice


Table name:

Figure 6: Mean Standing Systolic Blood Pressure Change from Baseline


Table name:
Table II. Clinically significant drug interactions with theophylline.Refer to PRECAUTIONS, Drug Interactions for further information regarding table.
 Drug  Type of Interaction  EffectAverage effect on steady-state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.
 Adenosine  Theophylline blocks adenosine receptors.  Higher doses of adenosine may be required to achieve desired effect.
 Alcohol  A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours  30% increase
 Allopurinol  Decreases theophylline clearance at allopurinol doses ≥ 600 mg/day  25% increase
 Aminoglutethimide  Increases theophylline clearance by induction of microsomal enzyme activity.  25% decrease
 Carbamazepine  Similar to aminoglutethimide.  30% decrease
 Cimetidine  Decreases theophylline clearance by inhibiting cytochrome P450 1A2.  70% increase
 Ciprofloxacin  Similar to cimetidine.  40% increase
 Clarithromycin  Similar to erythromycin.  25% increase
 Diazepam  Benzodiazepines increase CNS concentratrions of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors.  Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
 Disulfiram  Decreases theophylline clearance by inhibiting hydroxylation and demethylation.  50% increase
 Enoxacin  Similar to cimetidine.  300% increase
 Ephedrine  Synergistic CNS effects  Increased frequency of nausea, nervousness, and insomnia.
 Erythromycin  Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3.  35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
 Estrogen  Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance in unknown.  30% increase
 Flurazepam  Similar to diazepam.  Similar to diazepam.
 Fluvoxamine  Similar to cimetidine.  Similar to cimetidine.
 Halothane  Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines.  Increased risk of ventricular arrhythmias.
 Interferon, human recombinant alpha-A  Decreases theophylline clearance.  100% increase
 Isoproterenol (IV)  Increase theophylline clearance.  20% increase
 Ketamine  Pharmacologic  May lower theophylline seizure threshold.
 Lithium  Theophylline increases renal lithium clearance.  Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
 Lorazepam  Similar to diazepam.  Similar to diazepam.
 Methotrexate (MTX)  Decreases theophylline clearance.  20% increase after low dose MTX, higher dose MTX may have a greater effect.
 Mexiletine  Similar to disulfiram.  80% increase
 Midazolam  Similar to diazepam.  Similar to diazepam.
 Moricizine  Increases theophylline clearance.  25% increase
 Pancuronium  Theophylline may antagonize non-depolarizing neuromuscular blocking effects;possibly due to phosphodiesterase inhibition.  Larger dose of pancuronium may be required to achieve neuromuscular blockade.
 Pentoxifylline  Decreases theophylline clearance.  30% increase
 Phenobarbital (PB)  Similar to aminoglutethimide.  25% decrease after two weeks of concurrent PB.
 Phenytoin  Phenytoin increases theophylline clearance by increasing microsomal enzyme activity.  Serum theophylline and phenytoin concentrations decrease about 40%.
 Propafenone  Decreases theophylline clearance and pharmacologic interaction.  40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
 Propranolol  Similar to cimetidine and pharmacologic interaction.  100% increase Beta-2 blocking effect may decrease efficacy of theophylline.
 Rifampin  Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity.  20-40% decrease
 Sulfinpyrazone  Increase theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline.  20% increase
 Tacrine  Similar to cimetidine, also increases renal clearance of theophylline.  90% increase
 Thiabendazole  Decreases theophylline clearance.  190% increase
 Ticlopidine  Decreases theophylline clearance.  60% increase
 Troleandomycin  Similar to erythromycin.  33-100% increase depending on troleandomycin dose.
 Verapamil  Similar to disulfiram.  20% increase


Table name:
Drugs That Interfere with Hemostasis
Clinical Impact: • Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of naproxen or naproxen sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: Concomitant use of naproxen or naproxen sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen or naproxen sodium is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE-inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention: • During concomitant use of naproxen or naproxen sodium and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of naproxen or naproxen sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen or naproxen sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact: The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of naproxen or naproxen sodium and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of naproxen or naproxen sodium and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of naproxen or naproxen sodium and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of naproxen or naproxen sodium and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of naproxen or naproxen sodium and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention: The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of naproxen or naproxen sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of naproxen or naproxen sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact: Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention: Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen or naproxen sodium is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed release tablets are not recommended.
Cholestyramine
Clinical Impact: Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention: Concomitant administration of cholestyramine with naproxen or naproxen sodium is not recommended.
Probenecid
Clinical Impact: Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention: Patients simultaneously receiving naproxen or naproxen sodium and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact: Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention: Patients simultaneously receiving naproxen or naproxen sodium and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.


Table name:
Drug Interactions Associated with Increased Risk of  Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice Avoid grapefruit juice


Table name:
Drugs That Interfere with Hemostasis
  Clinical Impact: Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of celecoxib capsules with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ see Warnings and Precautions (5.11) ].
Aspirin
   Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ see Warnings and Precautions (5.2) ]. In two studies in healthy volunteers, and in patients with osteoarthritis and established heart disease respectively, celecoxib (200-400 mg daily) has demonstrated a lack of interference with the cardioprotective antiplatelet effect of aspirin (100-325 mg).
Intervention: Concomitant use of celecoxib capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions (5.11) ]. Celecoxib capsules are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
  Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
   Intervention: During concomitant use of celecoxib capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of celecoxib capsules and ACE-inhibitors or ARBs in patients who are elderly, volume- depleted, or have impaired renal function, monitor for signs of worsening renal function [ see Warnings and Precautions (5.6) ]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of celecoxib capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ see Warnings and Precautions (5.6) ].
Digoxin
Clinical Impact: The concomitant use of celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of celecoxib capsules and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of celecoxib capsules and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Celecoxib capsules have no effect on methotrexate pharmacokinetics.
Intervention: During concomitant use of celecoxib capsules and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of celecoxib capsules and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of celecoxib capsules and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ see Warnings and Precautions (5.2) ].
Intervention: The concomitant use of celecoxib with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of celecoxib capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of celecoxib capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.
NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.
In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
CYP2C9 Inhibitors or inducers
Clinical Impact: Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Co­-administration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of celecoxib.
Intervention Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers [ see Clinical Pharmacology (12.3) ].
CYP2D6 substrates
Clinical Impact: In vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6 (e.g. atomoxetine), and celecoxib may enhance the exposure and toxicity of these drugs.
Intervention Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2D6 substrates [ see Clinical Pharmacology (12.3) ].
Corticosteroids
Clinical Impact: Concomitant use of corticosteroids with celecoxib capsules may increase the risk of GI ulceration or bleeding.
Intervention Monitor patients with concomitant use of celecoxib capsules with corticosteroids for signs of bleeding [see Warnings and Precautions (5.2)].


Table name:
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin dailyFor patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice Avoid grapefruit juice


Table name:
Table 8: Clinically Significant Drug Interactions with Clarithromycin
Drugs That Are Affected By Clarithromycin
Drug(s) with Pharmacokinetics Affected by Clarithromycin Recommendation Comments
Antiarrhythmics:


 
Disopyramide
Quinidine
Dofetilide
Amiodarone
Sotalol
Procainamide
Not Recommended Disopyramide, Quinidine: There have been postmarketing reports of torsades de pointes occurring with concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QTc prolongation during coadministration of clarithromycin with these drugs [see Warnings and Precautions (5.3)] .

Serum concentrations of these medications should also be monitored. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with disopyramide and quinidine.

There have been postmarketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide. Therefore, blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide.


Digoxin Use With Caution Digoxin: Digoxin is a substrate for P-glycoprotein (Pgp) and clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are co-administered, inhibition of Pgp by clarithromycin may lead to increased exposure of digoxin. Elevated digoxin serum concentrations in patients receiving clarithromycin and digoxin concomitantly have been reported in postmarketing surveillance. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Monitoring of serum digoxin concentrations should be considered, especially for patients with digoxin concentrations in the upper therapeutic range.


Oral Anticoagulants:


   
Warfarin Use With Caution Oral anticoagulants: Spontaneous reports in the postmarketing period suggest that concomitant administration of clarithromycin and oral anticoagulants may potentiate the effects of the oral anticoagulants. Prothrombin times should be carefully monitored while patients are receiving clarithromycin and oral anticoagulants simultaneously [see Warnings and Precautions (5.4)] .


Antiepileptics:


   
Carbamazepine Use With Caution Carbamazepine: Concomitant administration of single doses of clarithromycin and carbamazepine has been shown to result in increased plasma concentrations of carbamazepine. Blood level monitoring of carbamazepine may be considered. Increased serum concentrations of carbamazepine were observed in clinical trials with clarithromycin. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with carbamazepine.


Antifungals:


 
Itraconazole Use With Caution Itraconazole: Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when administered concomitantly (see also Itraconazole under “Drugs That Affect Clarithromycin” in the table below). Clarithromycin may increase the plasma concentrations of itraconazole. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions.


Fluconazole No Dose Adjustment


Fluconazole: [see Pharmacokinetics (12.3)]
Anti-Gout Agents:


 
Colchicine (in patients with renal or hepatic impairment)


Contraindicated Colchicine: Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. The dose of colchicine should be reduced when co-administered with clarithromycin in patients with normal renal and hepatic function [see Contraindications (4.4) and Warnings and Precautions (5.4)] .


Colchicine (in patients with normal renal and hepatic function) Use With Caution
Antipsychotics:


 
Pimozide Contraindicated Pimozide: [See Contraindications (4.2)]


Quetiapine Quetiapine: Quetiapine is a substrate for CYP3A4, which is inhibited by clarithromycin. Co-administration with clarithromycin could result in increased quetiapine exposure and possible quetiapine related toxicities. There have been postmarketing reports of somnolence, orthostatic hypotension, altered state of consciousness, neuroleptic malignant syndrome, and QT prolongation during concomitant administration. Refer to quetiapine prescribing information for recommendations on dose reduction if co-administered with CYP3A4 inhibitors such as clarithromycin.


Antispasmodics:


   
Tolterodine (patients deficient in CYP2D6 activity) Use With Caution Tolterodine: The primary route of metabolism for tolterodine is via CYP2D6. However, in a subset of the population devoid of CYP2D6, the identified pathway of metabolism is via CYP3A. In this population subset, inhibition of CYP3A results in significantly higher serum concentrations of tolterodine. Tolterodine 1 mg twice daily is recommended in patients deficient in CYP2D6 activity (poor metabolizers) when co-administered with clarithromycin.


Antivirals:


   
Atazanavir Use With Caution Atazanavir: Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction (see Atazanavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)] .


Saquinavir (in patients with decreased renal function)   Saquinavir: Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A and there is evidence of a bi-directional drug interaction (see Saquinavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)] .


Ritonavir
Etravirine
  Ritonavir, Etravirine: (see Ritonavir and Etravirine under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)] .


Maraviroc   Maraviroc: Clarithromycin may result in increases in maraviroc exposures by inhibition of CYP3A metabolism. See Selzentry ® prescribing information for dose recommendation when given with strong CYP3A inhibitors such as clarithromycin.


Boceprevir (in patients with normal renal function)

Didanosine
No Dose Adjustment Boceprevir: Both clarithromycin and boceprevir are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when co-administered. No dose adjustments are necessary for patients with normal renal function (see Victrelis ® prescribing information).


Zidovudine   Zidovudine: Simultaneous oral administration of clarithromycin immediate-release tablets and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine concentrations. Administration of clarithromycin and zidovudine should be separated by at least two hours [see Pharmacokinetics (12.3)] .

The impact of co-administration of clarithromycin extended-release tablets or granules and zidovudine has not been evaluated.


Calcium Channel Blockers:


   
Verapamil Use With Caution Verapamil: Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent verapamil, [see Warnings and Precautions (5.4)] .


Amlodipine
Diltiazem


  Amlodipine, Diltiazem: [See Warnings and Precautions (5.4)]
Nifedipine   Nifedipine: Nifedipine is a substrate for CYP3A. Clarithromycin and other macrolides are known to inhibit CYP3A. There is potential of CYP3A-mediated interaction between nifedipine and clarithromycin. Hypotension and peripheral edema were observed when clarithromycin was taken concomitantly with nifedipine [see Warnings and Precautions (5.4)] .


Ergot Alkaloids:


   
Ergotamine
Dihydroergotamine
Contraindicated Ergotamine, Dihydroergotamine: Postmarketing reports indicate that coadministration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system [see Contraindications (4.6)] .


Gastroprokinetic Agents:


   
Cisapride Contraindicated Cisapride: [See Contraindications (4.2)]


HMG-CoA Reductase Inhibitors:


   
Lovastatin
Simvastatin
Contraindicated Lovastatin, Simvastatin, Atorvastatin, Pravastatin, Fluvastatin: [See Contraindications (4.5) and Warnings and Precautions (5.4)]

Atorvastatin
Pravastatin


Use With Caution  
Fluvastatin

No Dose Adjustment


 
Hypoglycemic Agents:


   
Nateglinide
Pioglitazone
Repaglinide
Rosiglitazone


Use With Caution Nateglinide, Pioglitazone, Repaglinide, Rosiglitazone: [See Warnings and Precautions (5.4) and Adverse Reactions (6.2)]

Insulin   Insulin: [See Warnings and Precautions (5.4) and Adverse Reactions (6.2)]


Immunosuppressants:


   
Cyclosporine Use With Caution Cyclosporine: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with cyclosporine.


Tacrolimus   Tacrolimus: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with tacrolimus.


Phosphodiesterase inhibitors:


   
Sildenafil
Tadalafil
Vardenafil
Use With Caution Sildenafil, Tadalafil, Vardenafil: Each of these phosphodiesterase inhibitors is primarily metabolized by CYP3A, and CYP3A will be inhibited by concomitant administration of clarithromycin. Co-administration of clarithromycin with sildenafil, tadalafil, or vardenafil will result in increased exposure of these phosphodiesterase inhibitors. Co-administration of these phosphodiesterase inhibitors with clarithromycin is not recommended. Increased systemic exposure of these drugs may occur with clarithromycin; reduction of dosage for phosphodiesterase inhibitors should be considered (see their respective prescribing information).


Proton Pump Inhibitors:


   
Omeprazole No Dose Adjustment Omeprazole: The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when coadministered with clarithromycin as a result of increased omeprazole exposures [see Pharmacokinetics (12.3)] (see also Omeprazole under “Drugs That Affect Clarithromycin” in the table below).


Xanthine Derivatives:


   
Theophylline Use With Caution Theophylline: Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serum theophylline concentrations [see Pharmacokinetics (12.3)] . Monitoring of serum theophylline concentrations should be considered for patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range.


Triazolobenzodiazepines and Other Related Benzodiazepines:


   
Midazolam Use With Caution Midazolam: When oral midazolam is co-administered with clarithromycin, dose adjustments may be necessary and possible prolongation and intensity of effect should be anticipated [see Warnings and Precautions (5.4) and Pharmacokinetics (12.3)] .


Alprazolam
Triazolam
  Triazolam, Alprazolam: Caution and appropriate dose adjustments should be considered when triazolam or alprazolam is co-administered with clarithromycin. There have been postmarketing reports of drug interactions and central nervous system (CNS) effects (e.g., somnolence and confusion) with the concomitant use of clarithromycin and triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested.

In postmarketing experience, erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines.


Temazepam
Nitrazepam
Lorazepam
No Dose Adjustment Temazepam, Nitrazepam, Lorazepam: For benzodiazepines which are not metabolized by CYP3A (e.g., temazepam, nitrazepam, lorazepam), a clinically important interaction with clarithromycin is unlikely.


Cytochrome P450 Inducers:


   
Rifabutin Use With Caution Rifabutin: Concomitant administration of rifabutin and clarithromycin resulted in an increase in rifabutin, and decrease in clarithromycin serum levels together with an increased risk of uveitis (see Rifabutin under “Drugs That Affect Clarithromycin” in the table below).


Other Drugs Metabolized by CYP3A:


   
Alfentanil
Bromocriptine
Cilostazol
Methylprednisole
Vinblastine
Phenobarbital
St. John’s Wort


Use With Caution There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with alfentanil, methylprednisolone, cilostazol, bromocriptine, vinblastine, phenobarbital, and St. John’s Wort.
Other Drugs Metabolized by CYP450 Isoforms Other than CYP3A:


   
Hexobarbital
Phenytoin
Valproate
Use With Caution There have been postmarketing reports of interactions of clarithromycin with drugs not thought to be metabolized by CYP3A, including hexobarbital, phenytoin, and valproate.


Drugs that Affect Clarithromycin
Drug(s) that Affect the Pharmacokinetics of Clarithromycin Recommendation Comments
Antifungals:


   
Itraconazole

Use With Caution Itraconazole: Itraconazole may increase the plasma concentrations of clarithromycin. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions (see also Itraconazole under “Drugs That Are Affected By Clarithromycin” in the table above).


Antivirals:


   
Atazanavir Use With Caution Atazanavir: When clarithromycin is co-administered with atazanavir, the dose of clarithromycin should be decreased by 50% [see Clinical Pharmacology (12.3)] .

Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with atazanavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium complex. Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.


Ritonavir (in patients with decreased renal function)   Ritonavir: Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with ritonavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium [see Pharmacokinetics (12.3)] .

Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.


Saquinavir (in patients with decreased renal function)   Saquinavir: When saquinavir is co-administered with ritonavir, consideration should be given to the potential effects of ritonavir on clarithromycin (refer to ritonavir above) [see Pharmacokinetics (12.3)] .


Etravirine   Etravirine: Clarithromycin exposure was decreased by etravirine; however, concentrations of the active metabolite, 14-OH-clarithromycin, were increased. Because 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered; therefore alternatives to clarithromycin should be considered for the treatment of MAC.


Saquinavir (in patients with normal renal function) No Dose Adjustment  
Ritonavir (in patients with normal renal function)


   
Proton Pump Inhibitors:


   
Omeprazole Use With Caution Omeprazole: Clarithromycin concentrations in the gastric tissue and mucus were also increased by concomitant administration of omeprazole [see Pharmacokinetics (12.3)] .


Miscellaneous Cytochrome P450 Inducers:


 
Efavirenz
Nevirapine
Rifampicin
Rifabutin
Rifapentine
Use With Caution Inducers of CYP3A enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine will increase the metabolism of clarithromycin, thus decreasing plasma concentrations of clarithromycin, while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. Alternative antibacterial treatment should be considered when treating patients receiving inducers of CYP3A. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with rifabutin (see Rifabutin under “Drugs That Are Affected By Clarithromycin” in the table above).


Table name:
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) Do not exceed 40 mg atorvastatin daily


Table name:
Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s) Recommendation Comments
Tizanidine Contraindicated Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)].
Theophylline Avoid Use (Plasma Exposure Likely to be Increased and Prolonged) Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate[see Warnings and Precautions (5.6).]
Drugs Known to Prolong QT Interval Avoid Use Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.10) and Use in Specific Populations (8.5)].
Oral antidiabetic drugs Use with caution Glucose-lowering effect potentiated Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs. [see Adverse Reactions (6.1).]
Phenytoin Use with caution Altered serum levels of phenytoin (increased and decreased) To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after coadministration of ciprofloxacin with phenytoin.
Cyclosporine Use with caution (transient elevations in serum creatinine) Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs Use with caution (Increase in anticoagulant effect) The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole Use with caution Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after coadministration with ciprofloxacin [see Warnings and Precautions (5.15)].
Clozapine Use with caution Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs Use with caution Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil Use with caution 2-fold increase in exposure Monitor for sildenafil toxicity (see Pharmacokinetics -(12.3)-].
Duloxetine Avoid Use 5-fold increase in duloxetine exposure If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products) Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2)]. Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels) Potentiation of ciprofloxacin toxicity may occur.


Table name:
Interacting Drug Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents Carefully monitor blood glucose (5.11, 7.3)


Table name:
Specific Drugs Reported
also: diet high in vitamin K unreliable PT/INR determinations †Increased and decreased PT/INR responses have been reported.

alcohol† aminoglutethimide amobarbital atorvastatin† azathioprine butabarbital butalbital carbamazepine chloral hydrate† chlordiazepoxide chlorthalidone









cholestyramine† clozapine corticotropin cortisone cyclophosphamide† dicloxacillin ethchlorvynol glutethimide griseofulvin haloperidol meprobamate









6-mercaptopurine methimazole† moricizine hydrochloride† nafcillin paraldehyde pentobarbital phenobarbital phenytoin† pravastatin† prednisone† primidone









propylthiouracil† raloxifene ranitidine† rifampin secobarbital spironolactone sucralfate trazodone vitamin C (high dose) vitamin K warfarin underdosage











Table name:
Table 25:  Clinically Important Drug Interactions with Aripiprazole:
Concomitant Drug Name or Drug Class
Clinical Rationale
Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine)
The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3) ].
With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION(2.7) ] .
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)
The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3) ] .
With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see DOSAGE AND ADMINISTRATION(2.7) ] .
Antihypertensive Drugs
Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.
Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.8) ] .
Benzodiazepines (e.g., lorazepam)
The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepamalone [see WARNINGS AND PRECAUTIONS (5.8 )]
Monitor sedation and blood pressure. Adjust dose accordingly.


Table name:
Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.Refer to PRECAUTIONS, Drug Interactions for information regarding table.
 albuterol,  famotidine  nizatidine
  systemic and inhaled  felodipine  norfloxacin
 amoxicillin  finasteride  ofloxacin
 ampicillin,  hydrocortisone  omeprazole
  with or without  isoflurane  prednisone, prednisolone
  sulbactam  isoniazid  ranitidine
 atenolol  isradipine  rifabutin
 azithromycin  influenza vaccine  roxithromycin
 caffeine,  ketoconazole  sorbitol
  dietary digestion  lomefloxacin  (purgative doses do not
 cefaclor  mebendazole  inhibit theophylline
 co-trimoxazole  medroxyprogesterone  absorption)
 (trimethoprim and  methylprednisolone  sucralfate
  sulfamethoxazole)  metronidazole  terbutaline, systemic
 diltiazem  metoprolol  terfenadine
 dirithromycin  nadolol  tetracycline
 enflurane  nifedipine  tocainide


Table name:
Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug Dosing Schedule Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio Change relative to reference) Risperidone Dose Recommendation
Coadministered Drug Risperidone AUC Cmax
Enzyme (CYP2D6) Inhibitors
Fluoxetine 20 mg/day 2 or 3 mg twice daily 1.4 1.5 Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine 10 mg/day 4 mg/day 1.3 - Re-evaluate dosing. Do not exceed 8 mg/day
20 mg/day 4 mg/day 1.6 -
40 mg/day 4 mg/day 1.8 -
Enzyme (CYP3A/PgP inducers) Inducers
Carbamazepine 573 ± 168 mg/day 3 mg twice daily 0.51 0.55 Titrate dose upwards. Do not exceed twice the patient's usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine 150 mg twice daily 1 mg single dose 1.2 1.4 Dose adjustment not needed
Cimetidine 400 mg twice daily 1 mg single dose 1.1 1.3 Dose adjustment not needed
Erythromycin 500 mg four times daily 1 mg single dose 1.1 0.94 Dose adjustment not needed
Other Drugs
Amitriptyline 50 mg twice daily 3 mg twice daily 1.2 1.1 Dose adjustment not needed


Table name:
AED  Co - administered
AED  Concentration
Topiramate  Concentration
Phenytoin
NCor25%increasea
48%decrease
Carbamazepine(CBZ)
NC
40%decrease
CBZepoxideb
NC 
            NE
Valproic acid
11%decrease
14%decrease
Phenobarbital
NC
            NE
Primidone
NC
           NE
Lamotrigine
NCatTPM dosesupto400  mg/day 
         13%decrease


Table name:
Interacting  Drug 
Interaction 
Multivalent cation-containing products including antacids, metal cations or didanosine 
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin 
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents 
Carefully monitor blood glucose (5.12, 7.3)


Table name: Use of sildenafil (REVATIO) is contraindicated when used for the treatment of PAH [see Contraindications (4)]. The following dose adjustments are recommended for use of tadalafil (ADCIRCA®) with LEXIVA: Coadministration of ADCIRCA in patients on LEXIVA: In patients receiving LEXIVA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Coadministration of LEXIVA in patients on ADCIRCA: Avoid use of ADCIRCA during the initiation of LEXIVA. Stop ADCIRCA at least 24 hours prior to starting LEXIVA. After at least one week following the initiation of LEXIVA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: LEXIVA: Sildenafil: 25 mg every 48 hours. Tadalafil: no more than 10 mg every 72 hours. Vardenafil: no more than 2.5 mg every 24 hours. LEXIVA/ritonavir: Sildenafil: 25 mg every 48 hours.Tadalafil: no more than 10 mg every 72 hours.Vardenafil: no more than 2.5 mg every 72 hours.Use with increased monitoring for adverse events.
Table 7. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class: Drug Name Effect on Concentration of Amprenavir or Concomitant Drug Clinical Comment
HCV/HIV-Antiviral Agents
HCV protease inhibitor: Telaprevira LEXIVA/ritonavir: ↓Amprenavir ↓Telaprevir Coadministration of LEXIVA/ritonavir and telaprevir is not recommended.
HCV protease inhibitor: Boceprevir LEXIVA/ritonavir: ↓Amprenavir (predicted) ↓Boceprevir (predicted) Coadministration of LEXIVA/ritonavir and boceprevir is not recommended. A pharmacokinetic interaction has been reported between boceprevir and some HIV protease inhibitors in combination with ritonavir, leading to decreased HIV protease inhibitor concentrations and, in some cases, decreased boceprevir concentrations.
Non-nucleoside reverse transcriptase inhibitor: Efavirenza LEXIVA: ↓Amprenavir LEXIVA/ritonavir: ↓Amprenavir Appropriate doses of the combinations with respect to safety and efficacy have not been established. An additional 100 mg/day (300 mg total) of ritonavir is recommended when efavirenz is administered with LEXIVA/ritonavir once daily. No change in the ritonavir dose is required when efavirenz is administered with LEXIVA plus ritonavir twice daily.
Non-nucleoside reverse transcriptase inhibitor: Nevirapinea LEXIVA: ↓Amprenavir ↑Nevirapine LEXIVA/ritonavir: ↓Amprenavir ↑Nevirapine Coadministration of nevirapine and LEXIVA without ritonavir is not recommended. No dosage adjustment required when nevirapine is administered with LEXIVA/ritonavir twice daily. The combination of nevirapine administered with LEXIVA/ritonavir once-daily regimen has not been studied.
HIV protease inhibitor: Atazanavira LEXIVA: Interaction has not been evaluated. LEXIVA/ritonavir: ↓Atazanavir ↔Amprenavir Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV protease inhibitors: Indinavira, nelfinavira LEXIVA: ↑Amprenavir Effect on indinavir and nelfinavir is not well established. LEXIVA/ritonavir: Interaction has not been evaluated. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV protease inhibitors: Lopinavir/ritonavira ↓Amprenavir ↓Lopinavir An increased rate of adverse events has been observed. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV protease inhibitor: Saquinavira LEXIVA: ↓Amprenavir Effect on saquinavir is not well established. LEXIVA/ritonavir: Interaction has not been evaluated. Appropriate doses of the combination with respect to safety and efficacy have not been established.
HIV integrase inhibitor: Raltegravira LEXIVA: ↓Amprenavir ↓Raltegravir LEXIVA/ritonavir: ↓Amprenavir ↓Raltegravir Appropriate doses of the combination with respect to safety and efficacy have not been established.
HIV CCR5 co-receptor antagonist: Maraviroca LEXIVA/ritonavir: ↓Amprenavir ↑Maraviroc No dosage adjustment required for LEXIVA/ritonavir. The recommended dose of maraviroc is 150 mg twice daily when coadministered with LEXIVA/ritonavir. LEXIVA should be given with ritonavir when coadministered with maraviroc.
Other Agents
Antiarrhythmics: Amiodarone, bepridil, lidocaine (systemic), and quinidine ↑Antiarrhythmics Use with caution. Increased exposure may be associated with life-threatening reactions such as cardiac arrhythmias. Therapeutic concentration monitoring, if available, is recommended for antiarrhythmics.
Anticoagulant: Warfarin Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants: Carbamazepine, phenobarbital, phenytoin Phenytoina LEXIVA: ↓Amprenavir LEXIVA/ritonavir: ↑Amprenavir ↓Phenytoin Use with caution. LEXIVA may be less effective due to decreased amprenavir plasma concentrations in patients taking these agents concomitantly. Plasma phenytoin concentrations should be monitored and phenytoin dose should be increased as appropriate. No change in LEXIVA/ritonavir dose is recommended.
Antidepressant: Paroxetine, trazodone ↓Paroxetine ↑Trazodone Coadministration of paroxetine with LEXIVA/ritonavir significantly decreased plasma levels of paroxetine. Any paroxetine dose adjustment should be guided by clinical effect (tolerability and efficacy). Concomitant use of trazodone and LEXIVA with or without ritonavir may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as LEXIVA, the combination should be used with caution and a lower dose of trazodone should be considered.
Antifungals: Ketoconazolea, itraconazole ↑Ketoconazole ↑Itraconazole Increase monitoring for adverse events. LEXIVA: Dose reduction of ketoconazole or itraconazole may be needed for patients receiving more than 400 mg ketoconazole or itraconazole per day. LEXIVA/ritonavir: High doses of ketoconazole or itraconazole (greater than 200 mg/day) are not recommended.
Anti-gout: Colchicine ↑Colchicine Patients with renal or hepatic impairment should not be given colchicine with LEXIVA/ritonavir. LEXIVA/ritonavir and coadministration of colchicine: Treatment of gout flares: 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.
If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.
Treatment of familial Mediterranean fever (FMF): Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). LEXIVA and coadministration of colchicine: Treatment of gout flares: 1.2 mg (2 tablets) x 1 dose. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg twice a day or 0.6 mg once a day.
If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once a day.
Treatment of FMF: Maximum daily dose of 1.2 mg (may be given as 0.6 mg twice a day).
Antimycobacterial: Rifabutina ↑Rifabutin and rifabutin metabolite A complete blood count should be performed weekly and as clinically indicated to monitor for neutropenia. LEXIVA: A dosage reduction of rifabutin by at least half the recommended dose is required. LEXIVA/ritonavir: Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (a maximum dose of 150 mg every other day or 3 times per week).
Benzodiazepines: Alprazolam, clorazepate, diazepam, flurazepam ↑Benzodiazepines Clinical significance is unknown. A decrease in benzodiazepine dose may be needed.
Calcium channel blockers: Diltiazem, felodipine, nifedipine, nicardipine, nimodipine, verapamil, amlodipine, nisoldipine, isradipine ↑Calcium channel blockers Use with caution. Clinical monitoring of patients is recommended.
Corticosteroid: Dexamethasone ↓Amprenavir Use with caution. LEXIVA may be less effective due to decreased amprenavir plasma concentrations.
Endothelin-receptor antagonists: Bosentan ↑Bosentan Coadministration of bosentan in patients on LEXIVA: In patients who have been receiving LEXIVA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Coadministration of LEXIVA in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of LEXIVA. After at least 10 days following the initiation of LEXIVA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Histamine H2-receptor antagonists: Cimetidine, famotidine, nizatidine, ranitidinea LEXIVA: ↓Amprenavir LEXIVA/ritonavir: Interaction not evaluated Use with caution. LEXIVA may be less effective due to decreased amprenavir plasma concentrations.
HMG-CoA reductase inhibitors: Atorvastatina ↑Atorvastatin Titrate atorvastatin dose carefully and use the lowest necessary dose; do not exceed atorvastatin 20 mg/day.
Immunosuppressants: Cyclosporine, tacrolimus, rapamycin ↑Immunosuppressants Therapeutic concentration monitoring is recommended for immunosuppressant agents.
Inhaled beta-agonist: Salmeterol ↑Salmeterol Concurrent administration of salmeterol with LEXIVA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.
Inhaled/nasal steroid: Fluticasone LEXIVA: ↑Fluticasone LEXIVA/ritonavir: ↑Fluticasone Use with caution. Consider alternatives to fluticasone, particularly for long-term use. May result in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression have been reported during postmarketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone. Coadministration of fluticasone and LEXIVA/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.
Narcotic analgesic: Methadone ↓Methadone Data suggest that the interaction is not clinically relevant; however, patients should be monitored for opiate withdrawal symptoms.
Oral contraceptives: Ethinyl estradiol/norethindronea LEXIVA: ↓Amprenavir ↓Ethinyl estradiol LEXIVA/ritonavir: ↓Ethinyl estradiol Alternative methods of non-hormonal contraception are recommended. May lead to loss of virologic response. a Increased risk of transaminase elevations. No data are available on the use of LEXIVA/ritonavir with other hormonal therapies, such as hormone replacement therapy (HRT) for postmenopausal women.
PDE5 inhibitors: Sildenafil, tadalafil, vardenafil ↑Sildenafil ↑Tadalafil ↑Vardenafil May result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH):
Proton pump inhibitors: Esomeprazolea, lansoprazole, omeprazole, pantoprazole, rabeprazole LEXIVA: ↔Amprenavir ↑Esomeprazole LEXIVA/ritonavir: ↔Amprenavir ↔Esomeprazole Proton pump inhibitors can be administered at the same time as a dose of LEXIVA with no change in plasma amprenavir concentrations.
Tricyclic antidepressants: Amitriptyline, imipramine ↑Tricyclics Therapeutic concentration monitoring is recommended for tricyclic antidepressants.


Table name:
Drugs That Increase Cyclosporine Concentrations
Calcium Channel Blockers Antifungals Antibiotics Glucocorticoids Other Drugs
diltiazem nicardipine verapamil   fluconazole itraconazole ketoconazole voriconazole   azithromycin clarithromycin erythromycin quinupristin/ dalfopristin   methylprednisolone   allopurinol amiodarone bromocriptine colchicine danazol imatinib metoclopramide nefazodoneoral contraceptives


Table name:
Table 2: Examples of CYP450 Interactions with Warfarin
 Enzyme  Inhibitors  Inducers
 CYP2C9  amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast  aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
 CYP1A2  acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton  montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
 CYP3A4  alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton  armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide


Table name:
 Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
 Interacting Agents  Prescribing Recommendations
 Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)  Avoid atorvastatin
 HIV protease inhibitor (lopinavir plus ritonavir)  Use with caution and lowest dose necessary
 Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)  Do not exceed 20 mg atorvastatin daily
 HIV protease inhibitor (nelfinavir)
Hepatitis C Protease inhibitor (boceprevir)
 Do not exceed 40 mg atorvastatin daily


Table name:
Interacting  Drug  
Interaction
Theophylline  
Serious and fatal reactions. Avoid concomitant use.  Monitor serum level (7)
Warfarin  
Anticoagulant effect enhanced. Monitor prothrombin  time, INR, and bleeding (7)
Antidiabetic agents  
Hypoglycemia including fatal outcomes have been  reported. Monitor blood glucose (7)
Phenytoin
Monitor phenytoin level (7)
Methotrexate 
Monitor for methotrexate toxicity (7)
Cyclosporine
May increase serum creatinine. Monitor serum  creatinine (7)
Multivalent cation-containing products including antacids,
metal cations or didanosine
Decreased ciprofloxacin absorption. Take 2 hours  before or 6 hours after ciprofloxacin for oral suspension (7)